Hostname: page-component-7c8c6479df-fqc5m Total loading time: 0 Render date: 2024-03-17T22:03:33.886Z Has data issue: false hasContentIssue false

Emerging roles of pathogens in Alzheimer disease

Published online by Cambridge University Press:  20 September 2011

Judith Miklossy*
Affiliation:
International Alzheimer Research Centre, Prevention Alzheimer Foundation, Martigny-Combe, Switzerland
*
*Corresponding author: Judith Miklossy, 1921 Martigny-Croix CP 16, 1921, Switzerland. E-mail: judithmiklossy@bluewin.ch
Rights & Permissions [Opens in a new window]

Abstract

Chronic spirochetal infection can cause slowly progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. There is a significant association between Alzheimer disease (AD) and various types of spirochete (including the periodontal pathogen Treponemas and Borrelia burgdorferi), and other pathogens such as Chlamydophyla pneumoniae and herpes simplex virus type-1 (HSV-1). Exposure of mammalian neuronal and glial cells and organotypic cultures to spirochetes reproduces the biological and pathological hallmarks of AD. Senile-plaque-like beta amyloid (Aβ) deposits are also observed in mice following inhalation of C. pneumoniae in vivo, and Aβ accumulation and phosphorylation of tau is induced in neurons by HSV-1 in vitro and in vivo. Specific bacterial ligands, and bacterial and viral DNA and RNA all increase the expression of proinflammatory molecules, which activates the innate and adaptive immune systems. Evasion of pathogens from destruction by the host immune reactions leads to persistent infection, chronic inflammation, neuronal destruction and Aβ deposition. Aβ has been shown to be a pore-forming antimicrobial peptide, indicating that Aβ accumulation might be a response to infection. Global attention and action is needed to support this emerging field of research because dementia might be prevented by combined antibiotic, antiviral and anti-inflammatory therapy.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2011

Alzheimer disease (AD) is characterised by a slowly progressive decline of memory and cognition. Alzheimer described the characteristic cortical senile plaques and neurofibrillary tangles in the brain of a 51-year-old woman with presenile dementia (Refs Reference Alzheimer1, Reference Alzheimer2). Because the presenile form, with onset before the age of 65, is identical to the most common form of senile dementia, today, the term AD is used for the designation of both presenile and senile cases (Refs Reference Katzman3, Reference Terry and Davies4).

Senile plaques were first described by Blocq and Marinesco (Ref. Reference Blocq and Marinesco5). Redlich (Ref. Reference Redlich6) first observed senile plaques in the brains of two patients with senile dementia. Recently, particularly from the use of the Gallyas silver technique (Ref. Reference Gallyas7), neuropil threads or curly fibres were recognised as further characteristic lesions of AD. Granulovacuolar degeneration is another typical alteration of neurons (Ref. Reference Simchowicz8). Other important features include neuronal and synaptic loss (Ref. Reference Terry9), Hirano bodies, reactive astrocytosis and microgliosis.

AD is a form of amyloidosis. The amyloid substance aggregated in the brain is a small, ~4 kDa amyloid beta peptide (Aβ). It is released by β- and γ-secretase cleavage from a larger 120 kDa transmembrane amyloid precursor protein (APP) (Refs Reference Kang10, Reference Selkoe11) and was purified and partially sequenced by Glenner and Wong (Ref. Reference Glenner and Wong12). APP exhibits features of a glycosylated cell-surface receptor and was shown to be a proteoglycan core protein (Ref. Reference Schubert13). APP is phylogenetically highly conserved and constitutively expressed by various cells other than neurons, including immune cells (Ref. Reference Bush, Beyreuther and Masters14). Human platelets, peripheral lymphocytes and leukocytes produce the major isoforms of APP, and after activation, they secrete amyloidogenic Aβ (Refs Reference Li15, Reference Allen16, Reference Mönning17, Reference Ledoux18).

1–42 has a higher ability to aggregate than the shorter Aβ1–40 (Refs Reference Jarrett and Lansbury19, Reference Kim and Hecht20). Aβ exists in soluble nontoxic monomers, strongly toxic soluble oligomers and in the form of less toxic insoluble fibrils. The soluble oligomers of Aβ1–42 are the most toxic (Refs Reference Lambert21, Reference Hartley22, Reference Walsh23, Reference Kirkitadze, Bitan and Teplow24, Reference Cerf25, Reference Pitt26). They form annular or pore-like structures that are indistinguishable from a class of pore-forming bacterial toxins (Refs Reference Kirkitadze, Bitan and Teplow24, Reference Cerf25, Reference Lashuel27), which cause rapid calcium influx through the targeted cell membranes (Refs Reference Rudel28, Reference Ayala29, Reference Müller30). Recent in vitro and in vivo studies showed that Aβ is an antimicrobial peptide (AMP) that targets bacterial membranes (Ref. Reference Soscia31). AMPs have proinflammatory activities and have a role in innate immune responses (Ref. Reference Soscia31).

Neurofibrillary tangles and neuropil threads contain paired helical filaments (PHFs) (Refs Reference Kidd32, Reference Terry33). The major component of PHFs is the microtubule-associated protein tau, which is in a pathological hyperphosphorylated state that abolishes microtubule assembly (Refs Reference Goedert, Trojanowski, Lee and Rosenberg34, Reference Lee35). Sequestration of peptidyl-prolyl cis/trans isomerase NIMA interacting 1 (PIN1) is one theory that explains the formation of these pathological fibrillar lesions (Ref. Reference Lu36).

Various hypotheses have been proposed to explain the pathogenesis of AD (Refs Reference Sherrington37, Reference Selkoe38, Reference Hardy39, Reference Tanzi and Bertram40, Reference Hardy and Selkoe41, Reference Bertram and Tanzi42, Reference Nagy43). A significant proportion of early-onset AD is inherited as an autosomal dominant trait (Ref. Reference Schellenberg44). Missense mutations of the APP gene located on chromosome 21 (Refs Reference Goate45, Reference Mullan46) are responsible for 5% of all early-onset familial AD cases (Ref. Reference Schellenberg44). Presenilin-1 (PS1) gene mutations are most frequent in early-onset familial AD (Refs Reference Sherrington37, 47). More than 80 different PS1 missense mutations or amino acid deletions have been identified (Refs Reference Sherrington37, 47, Reference Wasco48, Reference Perez-Tur49, Reference Miklossy50). Presenilin-2 (PS2) mutations are responsible for another subset of early-onset familial AD (Refs 47, Reference Levy-Lahad51). As originally shown by Hardy (Ref. Reference Hardy39), mutations in these pathogenic genes alter the processing of APP and result in an increase in amyloidogenic Aβ1–42 and Aβ1–43 (Refs Reference Miklossy50, Reference Citron52, Reference Cai, Golde and Younkin53, Reference Suzuki54, Reference Duff55, Reference Scheuner56, Reference Borchelt57, Reference Tomita58, Reference Citron59). The epsilon 4 allele of apolipoprotein E (APOE ɛ4) is an important risk factor for late-onset AD, which also correlates with increased Aβ burden (Ref. Reference Roses60). Finally, there is an association between AD and polymorphisms of various other genes, which include a growing number of genes, implicated in immune defence mechanisms (Refs Reference McGeer and McGeer61, Reference Bertram62).

The relation between the two major biological markers of AD, Aβ (Refs Reference Selkoe38, Reference Hardy and Selkoe41) and hyperphosphorylated tau (Refs Reference Goedert, Trojanowski, Lee and Rosenberg34, Reference Lee35), is not clear. Soluble Aβ and tau strongly interact (Ref. Reference Guo63), and APP is expressed in neurofibrillary tangles (Ref. Reference Perry64), suggesting that these apparently different pathologies are linked.

Alterations of various neurotransmitters, neuropeptides and hormones are reported to occur in AD (Refs Reference Davies, Katzman and Terry65, Reference Perry66, Reference Rossor67, Reference Fowler68). The cholinergic hypothesis is based on the alteration of acetylcholine synthesis, transport and release (Refs Reference Davies and Maloney69, Reference Bartus70). Oxidative damage to proteins, lipids and nucleic acids (Refs Reference Martins71, Reference Pappolla72, Reference Smith73, Reference Nunomura74) and mitochondrial dysfunction (Ref. Reference Parker75) are also significant contributors to the pathogenesis of AD. The role of various metals, including aluminium (Refs Reference Terry and Pena76, Reference Crapper, Krishnan and Dalton77) and iron (Ref. Reference Jellinger78) was proposed several decades ago. Direct modulation of APP processing by metal ions, including Ca2+, Zn2+, Fe2+/Fe3+ and Al3+, suggests that disrupted metal homeostasis also leads to increased APP levels (Ref. Reference Suh79). The calcium homeostasis hypothesis indicates that sustained deregulation of cytosolic calcium represents the common final pathway for neuronal death in AD (Ref. Reference Khachaturian80). Dysregulation of ubiquitylation or glycosylation processes (Refs Reference Mori, Kondo and Ihara81, Reference Lam82) has been shown in AD. Vascular lesions, including cerebral hypoperfusion and disturbed brain microcirculation, are also important factors (Refs Reference de la Torre and Mussivand83, Reference Esiri84, Reference Hachinski and Munoz85, Reference Snowdon86, Reference De Jong87, Reference Diaz88, Reference Kalaria89, Reference Suter90, Reference Miklossy91). Factors representing a risk for atherosclerosis (Refs Reference Muckle and Roy92, Reference Sparks93), are also risk factors for AD. Early involvement of the olfactory system in AD (Ref. Reference Averback94) led to the ‘olfactory hypothesis’, which suggests that putative pathogenic agents might access the brain by the olfactory pathways (Refs Reference Mann, Tucker and Yates95, Reference Hardy96, Reference Christen-Zaech97). Deregulation of various signalling pathways, apoptosis, craniocerebral trauma, exercise, environmental and nutritional factors, among others, are also implicated in the pathogenesis of AD.

The critical role of chronic inflammation and the importance of interleukin (IL)-1 signalling in AD is now widely recognised (Refs Reference McGeer98, Reference Griffin99, Reference McGeer and Rogers100). A series of inflammatory mediators, including cytokines, chemokines, proteases, adhesion molecules, free radicals, pentraxins, prostaglandins, anaphylatoxins and activated complement proteins, is present at the site of cortical lesions in AD (Refs Reference Schwab and McGeer101, Reference McGeer and McGeer102, Reference McGeer and McGeer103). The membrane attack complex (MAC, C5b-9) is also associated with plaques, tangles and neuropil threads (Refs Reference McGeer and Rogers100, Reference Webster104). Use of nonsteroidal anti-inflammatory drugs reduces the risk of AD (Refs Reference Stewart105, Reference Zandi106, Reference Veld107, Reference Akiyama108).

Nearly a century ago, Fischer, Alzheimer and their colleagues (Refs Reference Alzheimer2, Reference Fischer109) discussed the possibility that microorganisms could have a role in the formation of senile plaques. That a slow-acting unconventional infectious agent, acquired at an early age and requiring decades to become active, might be involved in AD was considered by several authors (Refs Reference Wisniewsky, Katzman, Terry and Bick110, Reference Khachaturian111). A growing number of recent observations indicate that infectious agents are involved in the pathogenesis of AD. Here, I review historical and recent observations on infectious agents related to AD and analyse the significance of the association and causal relationship.

Analogies between AD and the atrophic form of general paresis

Historical observations show that the clinical and pathological hallmarks defining AD are similar to those occurring in the atrophic form of general paresis, a chronic bacterial infection (Refs Reference Hübner112, Reference Perusini113, Reference Pacheco e Silva114, Reference Pacheco e Silva115, Reference Schlossberger, Brandis, Lubarsch, Henke and Roessle116, Reference Rizzo117, Reference Miklossy, Duyckaerts and Litvan118). In 1913, Noguchi and Moore (Ref. Reference Noguchi and Moore119) provided conclusive evidence that spirochetes are responsible for slowly progressive dementia, cortical atrophy and local amyloidosis.

General paresis of the insane, paretic dementia or dementia paralytica is a chronic meningoencephalitis caused by the direct invasion of brain parenchyma by Treponema pallidum. Two forms are distinguished: the infiltrative and the atrophic form (Refs Reference Pacheco e Silva114, Reference Rizzo117). In the infiltrative form, mood disorders and psychosis predominate, and lymphoplasmocytic meningoencephalitis is the characteristic pathology (Refs Reference Rizzo117, Reference Miklossy, Duyckaerts and Litvan118). The atrophic form is characterised by slowly progressive dementia and cortical atrophy, which is accentuated in the frontotemporal regions (Refs Reference Pacheco e Silva114, Reference Pacheco e Silva115). Spirochetes form masses, plaques or colonies (Fig. 1) and disseminate as individual filaments, which are restricted to the cerebral cortex (Fig. 1) (Refs Reference Pacheco e Silva114, Reference Pacheco e Silva115). These spirochetal masses and individual spirochetes are morphologically identical to senile plaques (Fig. 1) and neuropil threads (Fig. 1). Pacheco e Silva (Refs Reference Pacheco e Silva114, Reference Pacheco e Silva115), reported that the number of spirochetes and spirochetal ‘plaques’, which are numerous in the hippocampus and frontal cortex, increases in parallel with the severity of cortical atrophy (Refs Reference Pacheco e Silva114, Reference Pacheco e Silva115). Lymphoplasmocytic infiltrates are absent. Severe neuron loss is accompanied by reactive microgliosis and astrocytosis and by accumulation of ‘paralytic iron’ (Ref. Reference Merritt, Adams and Solomon120). The occurrence of neurofibrillary tangles is also documented in general paresis (Refs Reference Perusini113, Reference Miklossy, Duyckaerts and Litvan118, Reference Bonfiglio121, Reference Vinken and Bruyn122), and the local amyloid (Ref. Reference Volland123), as in AD, consists of Aβ (Ref. Reference Miklossy, Rosemberg and McGeer124).

Figure 1. Distribution of spirochetes in the atrophic form of general paresis and in the frontal cortex of an Alzheimer disease (AD) patient with Lyme neuroborreliosis. Spirochetes form plaque-like masses (a,c) and disseminate as individual filaments (b,d) in general paresis (a,b) and AD (c,d), which are identical to senile plaques and curly fibres. (a,c) Bosma Steiner silver technique for the visualisation of spirochetes. (b) T. pallidum-specific polyclonal antibody. (d) Gallyas silver technique. Scale bars: 50 µm (a), 40 µm (c), 10 µm (b,d). All images were obtained from previously published studies: a (Ref. Reference Miklossy, Rosemberg and McGeer124); b (Ref. Reference Miklossy175); c, d (Ref. Reference Miklossy149).

Analogies between AD and other age-related chronic inflammatory disorders

Pathogens can produce slowly progressive chronic diseases. Following the pioneering work of Warren and Marshall (Ref. Reference Marshall and Warren125), it is today established that Helicobacter pylori causes stomach ulcers. Infectious agents are also linked to atherosclerosis, cardio- and cerebrovascular disorders (Refs Reference Laitinen126, Reference Saikku127, Reference Mendall128, Reference Martin de Argila129, Reference Renvert130, Reference Zaremba131, Reference Chiu132, Reference Haraszthy133, Reference Rassu134), chronic lung diseases (Refs Reference Martin135, Reference MacDowell and Bacharier136, Reference Micillo137), inflammatory bowel diseases and neuropsychiatric disorders (Refs Reference Marttila138, Reference Rott139, Reference Beaman and Caino140, Reference Gosztonyi and Ludwig141, Reference Salvatore142, Reference Langford and Masliah143).

Chlamydophila (Chlamydia) pneumoniae (Refs Reference Laitinen126, Reference Saikku127), H. pylori (Refs Reference Mendall128, Reference Martin de Argila129) and several periodontal pathogens, including invasive oral spirochetes (Refs Reference Renvert130, Reference Zaremba131) and herpes viruses, have been found in human atherosclerotic lesions. Some of them also enhanced atherosclerosis in experimental animals (Refs Reference Zaremba131, Reference Chiu132). These pathogens were also reported to be associated with AD (Refs Reference Balin144, Reference Balin145, Reference Miklossy146, Reference Riviere, Riviere and Smith147, Reference Miklossy148, Reference Miklossy149, Reference Jamieson150, Reference Itzhaki and Wozniak151).

Epidemiological studies have confirmed that several of these chronic inflammatory disorders are associated with AD (Refs Reference Olichney152, Reference Luchsinger153, Reference Voisin154, Reference Ott155). In addition, they are all linked to periodontal polybacterial disorders, which are primarily caused by Gram-negative bacteria (Refs Reference Kamer156, Reference Pihlstrom, Michalowicz and Johnson157, Reference Gibson158, Reference Mattila, Pussinen and Paju159). Spirochetes and herpes viruses are predominant periodontal pathogens (Refs Reference Seppaa and Ainamo160, Reference Ling161, Reference Heydenrijk162, Reference O'Brien-Simpson163), and C. pneumoniae is a major upper respiratory tract pathogen. An infectious origin might give a comprehensive explanation of the common cellular and molecular mechanisms, inflammatory processes and common inflammatory gene polymorphisms involved in these chronic inflammatory disorders and AD (Refs Reference McGeer and McGeer61, Reference DeGraba164, Reference Kolb and Mandrup-Poulsen165).

Evidence for the association of pathogens with AD

Spirochetes

Spirochetes are Gram-negative, helical bacteria, which possess endoflagella, taxonomically distinguishing them from other bacteria. There are over 200 different spirochetal species or phylotypes (Ref. Reference Dewhirst166). Spirochetes are causative agents of important human diseases such as syphilis, pinta, yaws, bejel, Lyme disease, Vincent angina, relapsing fever, leptospirosis, ulcerative gingivitis and various periodontal disorders (Ref. Reference Gastinel167). The major Borrelia species causing Lyme disease are B. burgdorferi (Ref. Reference Burgdorfer170), B. afzelii, B. garinii and B. valaisiana. Relapsing fever is caused by B. recurrentis. Oral spirochetes are predominant periodontal pathogens that are highly prevalent in the population and comprise diverse Treponema species (Refs Reference Dewhirst166, Reference Chan171). Several are invasive (Refs Reference Riviere172, Reference Peters173): they include T. denticola, T. socranskii, T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium and T. putidum (Refs Reference Dewhirst166, Reference Chan171, Reference Wyss174). T. vincentii causes Vincent angina, a necrotising fusospirochetal disease (Ref. Reference Gastinel167).

Because spirochetes are strongly neurotropic (Ref. Reference Gastinel167), it was expected that several types of spirochetes, in an analogous way to T. pallidum, might cause dementia, plaque- and tangle-like lesions, Aβ deposition and consequently might be involved in the pathogenesis of AD. To detect all types of spirochete, neutral techniques need to be used (Ref. Reference Miklossy146). Using dark-field microscopy, spirochetes were detected in the cerebrospinal fluid (CSF), in the blood and in the brain in 14 definite AD cases tested (Table 1). Spirochetes were not found in 13 age-matched controls without any AD-type cortical changes (Ref. Reference Miklossy146). Silver-stained helically shaped spirochetes were also detected by electron microscopy. Spirochetes were isolated from the cerebral cortex in these 14 AD cases (Table 1), and in three of them, they were cultivated from the brain in a selective medium for B. burgdorferi (Ref. Reference Miklossy146). Spirochetes were detected and isolated from the brains of eight additional AD cases derived from another laboratory and in the blood of five living patients with clinically diagnosed AD-type dementia (Ref. Reference Miklossy, Giacobini and Becker186; Table 1). Four healthy controls did not show spirochetes. Taxonomical analyses showed that the helically shaped microorganisms belong to the order Spirochaetales (Ref. Reference Miklossy187). To ensure the consistency of these results, the detection of spirochetes was also performed using various other techniques, including histochemistry, dark-field microscopy, atomic force microscopy, electron microscopy and immunoelectron microscopy, immunohistochemistry using spirochete and bacterial peptidoglycan (PGN)-specific antibodies (Refs Reference Miklossy146, Reference Riviere, Riviere and Smith147, Reference Miklossy149, Reference Miklossy, Giacobini and Becker186, Reference Miklossy187, Reference Miklossy176, Reference Miklossy175, Reference Miklossy188, Reference Miklossy189), and detection of specific and nonspecific bacterial DNA (Refs Reference Miklossy149, Reference Miklossy176). PGN is the building block of the cell wall of Gram-negative and Gram-positive bacteria; however, mycoplasma and chlamydiae lack detectable PGN (Refs Reference Hesse190, Reference McCoy191). The morphology of spirochetes detected by spirochete- or PGN-specific antibodies is identical (Fig. 2; compare also Fig. 7 G and H of Ref. Reference Miklossy175). PGN-immunoreactive spirochetes were detected in 32 definite AD cases and in 12 cases with mild or moderate AD-type cortical changes.

Figure 2. Spirochetes detected in the frontal cortex of neuropathologically confirmed Alzheimer disease cases. Spirochetes in an immature senile plaque detected by a cocktail of antibodies against Borrelia burgdorferi (a), in a mature plaque detected by in situ hybridisation (b, arrows) using Borrelia-specific probes, and in an amorphous plaque detected by antibacterial peptidoglycan antibody (c). (d) The central part of panel c at higher magnification. Arrows indicate helical spirochetes with the same morphology as observed in b. Scale bars: 80 µm (a), 30 µm (b), 80 µm (c), 20 µm (d). Images are from previously published studies: a,b (Ref. Reference Miklossy149); c,d (Ref. Reference Miklossy188).

Table 1. Detection of spirochetes in AD

Data reviewed in the literature with respect to the detection of all types of spirochetes using neutral techniques and the specific detection of periodontal pathogen Treponemas and Bb. Results of the statistical analysis are given for each group and for all studies together. AD indicates number of AD cases positive for spirochetes/ number of AD cases analysed; Control indicates number of control cases positive for spirochetes/number of control cases analysed. AD, Alzheimer disease; Bl, blood; CSF, cerebrospinal fluid; EM, electron microscopy; AFM, atomic force microscopy; DF, dark-field microscopy; HC, histochemistry (Warthin and Starry, Bosma-Steiner silver stain for spirochetes); IHC, immunohistochemistry; ISH, in situ hybridisation; PCR, polymerase chain reaction; Bb, Borrelia burgdorferi; Wbl, Western blot; P is exact value of the significance calculated by Fischer test; OR, odds ratio; CI, 95% confidence interval; +, positive; –, negative; ND, not determined; seq, sequencing.

aControls without any AD-type changes.

bCases from previous studies, which were subtracted when the total number of cases of studies was considered.

cCases with mild or moderate AD-type cortical changes.

dWhere the number of positive controls was zero, in order to calculate the OR and 95% CI, one positive case was added to the control group.

Other authors found no evidence of spirochetes in the brains of seven AD cases by dark-field or electron microscopy (Ref. Reference McLaughlin192). However, spirochetes were observed in the blood of one of 22 living patients with AD-type dementia (Table 1). The spirochete observed by these authors corresponded to the vegetative, regularly spiral form. They suggested that it could correspond to an oral spirochete. Whether the atypical, pleomorphic spirochetal forms, which commonly occur in infected tissues, blood and CSF (Refs Reference Gastinel167, Reference Miklossy175, Reference Jacquet and Sézary177, Reference Mattman193), were considered by the authors is not clear.

Periodontal pathogen Treponemas

Using molecular and immunological techniques, six of seven periodontal Treponema species, namely T. socranskii, T. pectinovorum, T. denticola, T. medium, T. amylovorum and T. maltophilum, were identified in the brains of AD patients using species-specific polymerase chain reaction (PCR; Table 1). At least one oral Treponema species was present in 14 of 16 AD brains, compared with 4 out of 18 controls (Ref. Reference Riviere, Riviere and Smith147). T. pectinovorum and T. socranskii antigens were observed in 15 of 16 AD brains and in 7 of 18 controls. In the hippocampus and in the frontal cortex. Six different Treponema species were detected in one AD patient, five species in four, four or three species each in one AD case, and one species in seven AD brains. Two Treponema species were observed in one control and one species in the other three positive controls. These results reinforce previous observations (Ref. Reference Miklossy146) and indicate that these periodontal pathogen spirochetes, in an identical way to T. pallidum and B. burgdorferi, have the ability to invade the brain, persist in the brain, and cause dementia, cortical atrophy and amyloid deposition.

Borrelia burgdorferi

The causative agent of Lyme disease is transmitted by the bite of infected ticks (Ref. Reference Burgdorfer170). Neurological complications occur in about 15% of affected individuals. Dementia and subacute presenile dementia both occur in Lyme disease (Refs Reference Miklossy146, Reference Miklossy149, Reference MacDonald194, Reference Dupuis195, Reference Schaeffer196, Reference Fallon and Nields197, Reference Pennekamp and Jaques198). B. burgdorferi was first detected in the brains of two AD patients (Table 1) by MacDonald and Miranda (Ref. Reference MacDonald and Miranda178) and MacDonald (Ref. Reference MacDonald199). This spirochete was detected in the cerebral cortex by dark-field microscopy and with a specific antibody against B. burgdorferi. This species was also detected and cultivated from the brains of three definite AD cases in an initial series of 14 AD cases (Ref. Reference Miklossy146). Molecular characterisation, using 16S rRNA gene sequence analysis, identified these spirochetes as B. burgdorferi sensu stricto (s.s.) (Ref. Reference Miklossy149). Electron microscopy analysis confirmed that these spirochetes possess 10–15 endoflagella typical of Borrelia species. Two of the three AD patients had a positive CSF serology for B. burgdorferi, and the 31 kDa outer surface protein A (OspA) band, which is highly specific for B. burgdorferi, was detected by western blot in these three AD cases (Ref. Reference Miklossy149). The pathological changes found in the brain were identical to those occurring in the atrophic form of general paresis (Ref. Reference Miklossy149). The cortical distribution of spirochetes in masses or colonies was identical to those of senile plaques, and the morphology of individual spirochetes was identical to those of curly fibres (Ref. Reference Miklossy149). B. burgdorferi antigens colocalised with Aβ in cortical plaques and in leptomeningeal and cortical arteries containing amyloid deposits. Neurofibrillary tangles were also immunoreactive for B. burgdorferi. OspA and flagellin genes were detected in AD-type lesions using in situ hybridisation (ISH) (Fig. 2b). In additional AD patients with concurrent Lyme neuroborreliosis, B. burgdorferi-specific antigens (Ref. Reference Miklossy146) and DNA (Ref. Reference Meer-Scherrer179) were observed. Using species-specific PCR, B. burgdorferi DNA was detected in 5 of 16 AD patients tested and in 1 of 18 controls, all of which also had oral Treponema spirochetes (Ref. Reference Riviere, Riviere and Smith147). Finally, B. burgdorferi-specific DNA was detected by both ISH and PCR in the hippocampus in 7 of 10 pathologically confirmed AD cases (Refs Reference MacDonald183, Reference MacDonald184) (Table 1).

Pappolla and colleagues (Ref. Reference Pappolla185) failed to detect B. burgdorferi in six AD patients. They stated that they could not exclude other spirochetes not detected by their methods. In all other studies where B. burgdorferi was not detected, evidence is lacking on whether the analysed AD patients had Lyme neuroborreliosis or not (Refs Reference Gutacker180, Reference Marques181) (Table 1). Similarly, the analysis of the serology of B. burgdorferi alone, as a result of the low incidence of Lyme dementia compared with AD, might give false-negative results (Refs Reference Gutacker180, Reference Galbussera182). To demonstrate the role of B. burgdorferi, AD patients with Lyme neuroborreliosis should be analysed.

Taken together, these observations show that various authors detected and cultivated various types of spirochetes from the brains of AD patients. Coinfection with several types of spirochetes occurs.

Chlamydophyla pneumoniae

Several authors reported the existence of an association between C. pneumoniae, an obligate intracellular respiratory pathogen, and AD (Refs Reference Balin144, Reference Gérard200, Reference Gérard201, Reference Paradowski202, Reference Appelt203) (Table 2). C. pneumoniae-specific DNA was detected in the brains in 90% of sporadic AD patients and in 5% of controls (Ref. Reference Balin144) (Table 2). Two mRNAs, encoding KDO transferase and a 376 kDa protein, specific to C. pneumoniae, were also identified in frozen AD brain tissue by reverse transcriptase-PCR (RT-PCR).

Table 2. Detection of Chlamydophyla pneumoniae and other bacteria in AD

AD, number of AD cases with positive detection/number of AD cases analysed; Control, number of control cases with positive detection/number of control cases analysed; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase-PCR; EM, electron microscopy; IHC, immunohistochemistry; Cult, culture. P, exact value of significance following Fischer test; OR, odds ratio; CI, 95% confidence interval values. aPositive in at least one of several samples.

Immunohistochemical analyses of AD brains showed C. pneumoniae in microglia, perivascular macrophages and astrocytes, and in about 20% of neurons (Refs Reference Balin144, Reference Gérard200, Reference Gérard201, Reference Appelt203, Reference Hudson and Dolmer207, Reference MacIntyre211). They were commonly found in brain regions showing the characteristic neuropathology of AD (Refs Reference Balin144, Reference Gérard200, Reference Gérard201). The presence of C. pneumoniae in the brains of AD patients was also confirmed by immunoelectron microscopy using specific monoclonal antibody against the outer membrane protein of C. pneumoniae. Electron and immunoelectron microscopy identified both chlamydial elementary bodies and reticulate bodies (RBs) (Refs Reference Albert212, Reference Balin144). That the replicative RB form was also detected in glial cells, neurons and pericytes indicates that a viable and transcriptionally active form of the microorganism is present in these cells (Refs Reference Gérard201, Reference Arking213, Reference Dreses-Werringloer214, Reference Dreses-Werringloer215). Pleomorphic forms of C. pneumoniae were also observed (Ref. Reference Arking213). C. pneumoniae-specific DNA was detected in the CSF in a significantly higher number of cases in AD patients (43.9%) than in controls (10.6%) (Ref. Reference Paradowski202). C. pneumoniae was cultured from various brain samples of AD patients originating from different geographic regions of North America (Refs Reference Balin144, Reference Gérard201, Reference Dreses-Werringloer215) and was also isolated from the CSF (Ref. Reference Paradowski202). Tor-1 and Phi-1 isolates were characterised by PCR assays targeting C. pneumoniae-specific genes Cpn0695, Cpn1046 and tyrP. Two groups, using paraffin-embedded brain samples, failed to detect C. pneumoniae in AD or in controls by PCR (Refs Reference Nochlin216, Reference Gieffers217). In another study, C. pneumoniae was detected in 2 of 15 AD cases and in 1 of 5 controls (Ref. Reference Ring and Lyons204).

Other bacteria

Propionibacterium acnes, an atypical anaerobic bacterium, was identified in biopsy specimens of the frontal cortex in three of four AD patients and in one of five controls with cerebral tumour. The P. acnes positive control was an elderly patient with cardiovascular risk factors and glioblastoma (Ref. Reference Kornhuber205). P. acnes was identified by microbiological methods and by gas chromatography. The bacterium was cultivated from frontal cortical biopsy specimens in Schaedler blood agar, at 35°C, under anaerobic conditions (Refs Reference Kornhuber205, Reference Kornhuber206). P. acnes has long been considered to be a commensal bacillus of the skin. Recent observations showed that P. acnes, the causative agent of acne vulgaris, is implicated in various infections, including brain abscesses, endocarditis, endophthalmitis and osteomyelitis (Refs Reference Delahaye208, Reference Brook209). P. acnes was also shown to be a predominant periodontal pathogen (Ref. Reference Preza218). By haematogenous dissemination, it can reach and infect various organs, including the brain. Stabilisation of the clinical symptoms and memory improvement were observed in two AD cases treated with P. acnes-sensitive cephalosporine combined with enalapril and oestrogen (Ref. Reference Kornhuber206). The author pointed to microangiopathy as the underlying pathology (Refs Reference Kornhuber219, Reference Kornhuber220). Because the number of AD cases analysed is low, further studies should be encouraged to determine any association of P. acnes with AD.

Actinomycetes have also been suggested to be involved in AD, with an incidence four times higher than in other pathological conditions (Ref. Reference Howard and Pilkington221). Ultrastructural analysis revealed that the fibronectin-immunopositive fibrillary lesions in senile plaques, which were negative for neuronal, glial and macrophage markers, are compatible with filamentous microorganisms and might correspond to Actinomycetes (Ref. Reference Howard and Pilkington221). It is noteworthy that Actinobacillus actinomycetemcomitans is a frequent periodontal pathogen (Ref. Reference Fenesy222) and that Nocardia asteroides was reported to cause Parkinson-like symptoms in experimental animals (Ref. Reference Kohbata and Beaman223).

Finally, the causative agent of stomach ulcers, H. pylori (Ref. Reference Marshall and Warren125), has also been suggested to be associated with AD (Refs Reference Malaguarnera224, Reference Kountouras225, Reference Kountouras226). Serum IgG and IgA antibodies against H. pylori occurred in a higher percentage in the group of 30 AD patients compared with 30 controls (Ref. Reference Malaguarnera224). The difference is statistically significant as determined by post-hoc comparison (Ref. Reference Honjo, van Reekum and Verhoeff210). An almost twofold higher prevalence of gastric H. pylori infection was observed in clinically diagnosed AD patients and in patients with mild cognitive decline (Refs Reference Kountouras225, Reference Kountouras227) than in controls. H. pylori-specific IgG antibody levels were also significantly higher in the blood and CSF of AD patients than in controls (Ref. Reference Kountouras226). Additional studies would be of interest in detecting whether H. pylori is present in the brain and to analyse the possibility of a causal relationship between H. pylori and AD.

Herpes simplex virus type-1 (HSV-1) and other viruses

HSV-1 is a common neurotropic virus that infects around 70% of the population after the age of 50 (Refs Reference Jamieson150, Reference Jamieson228, Reference Bertrand229, Reference Xu230). HSV-1 DNA was detected (Table 2) in brain samples using ISH in some elderly patients with dementia (Ref. Reference Sequiera231). Three other studies failed to detect HSV-1 by ISH in AD or in control brains (Refs Reference Middleton232, Reference Pogo and Elizan233, Reference Pogo, Casals and Elizan234, Reference Walker, O'Kusky and McGeer235). Increasing numbers of recent observations have detected HSV-1 DNA in the brain in AD (Refs Reference Jamieson150, Reference Itzhaki and Wozniak151, Reference Jamieson228, Reference Bertrand229, Reference Itzhaki236, Reference Itabashi237, Reference Lin238). Using PCR, Jamieson et al. (Ref. Reference Jamieson150) observed HSV-1 DNA in the brains of a high proportion of elderly subjects, with or without AD, which was absent or less frequent in young controls (Ref. Reference Jamieson228). Several authors showed that HSV-1 is a significant risk factor (Table 3) when present in AD patients who are carriers of APOE ɛ4 (Refs Reference Itzhaki236, Reference Itabashi237, Reference Lin238), but this is not supported by Beffert et al. (Refs Reference Beffert239, Reference Beffert240). In situ PCR showed that HSV-1 DNA is localised to senile plaques (Ref. Reference Renvoize, Awad and Hambling243). Ninety per cent of senile plaques in AD and 80% in normal ageing subjects contained viral DNA (Ref. Reference Wozniak, Mee and Itzhaki241).

Table 3. Detection of HSV-1 in AD

Number of Alzheimer cases with positive detection/number of Alzheimer cases analysed; Control, number of control cases with positive detection/number of control cases analysed. P, value of significance following Fischer test; OR, odds ratio; CI, 95% confidence interval values; +, positive; –, negative; AD, Alzheimer disease; CSF, cerebrospinal fluid; HSV-1, herpes simplex virus type-1; IHC, immunohistochemistry; ISH, in situ hybridisation; PCR, polymerase chain reaction; APOE ɛ4: epsilon 4 allele of apolipoprotein E.

Anti-HSV-1 antibodies as detected in the CSF by enzyme-linked immunosorbent assay (ELISA) were also significantly higher in AD patients than in younger controls, but without a significant difference between the AD and age-matched control groups (Ref. Reference Wozniak242). Increased titres of HSV-1 IgGs, which characterise past infection, were observed in AD cases and age-matched controls, without a significant difference between the two groups (Refs Reference Renvoize, Awad and Hambling243, Reference Ounanian244). In a large prospective study, in addition to HSV-1 IgG, the presence of IgM, which characterises active primary infection or reactivation of the infection, was also assessed in the sera of 512 elderly patients, initially free of dementia. During 14 years of follow-up, 77 AD cases were diagnosed. In contrast to IgG, IgM-positive subjects showed a significantly higher risk of developing AD, indicating that reactivation of HSV-1 seropositivity is correlated with AD (Ref. Reference Letenneur245).

Other herpes viruses were also detected in the brain using PCR: human herpes virus 6 (HHV6) types A and B, herpes simplex virus type-2 (HSV-2) and cytomegalovirus (CMV). HHV6, HSV-2 and CMV were observed in 70%, 13% and 36% of AD patients and in 40%, 20% and 35% of controls, respectively. The differences between the groups were not statistically significant (Ref. Reference Lin246).

In addition to CMV, a possible association between HLA-BW15 and AD has also been reported (Ref. Reference Renvoize247). A recent study revealed that elderly subjects with high levels of antibody against CMV develop more severe cognitive decline over 4 years (Ref. Reference Aiello248) compared with controls.

The adenovirus early region 1A (E1A) gene and its expression using ISH and immunohistochemistry were analysed in five AD cases and in two controls. Reactive microglial cells in both AD (5/5) and control brain tissue (2/2) showed positive hybridisation and immunoreactive expression of adenovirus E1A, indicating a monocyte- or microglia-mediated entry of adenovirus into the central nervous system (CNS) (Ref. Reference Matsuse249).

Borna disease virus (BDV) was linked to affective disorders and schizophrenia (Refs Reference Rott139, Reference Salvatore142). A few attempts have been made to analyse the prevalence of BDV antibodies and BDV p40 gene coding sequences in AD (Refs Reference Igata250, Reference Yamaguchi251, Reference Chalmers, Thomas and Salmon252), which did not show an association (Table 3). Following Borna-virus-induced infection in APP(Tg2576) transgenic mice, a reduction of cortical and hippocampal Aβ deposits was observed (Ref. Reference Stahl253). One explanation is that the stimulation and activation of microglia might produce this effect.

The human immunodeficiency virus type-1 (HIV-1) (Ref. Reference Rempel and Pulliam254) is able to induce the biological hallmarks of AD; however, the virus is present in the brains of mostly young patients suffering from acquired immune deficiency syndrome (AIDS). The virus invades mostly macrophages and glial cells and the virus itself does not reproduce the pathological hallmarks of AD. However, by affecting immune defences, HIV-1 facilitates infection by various pathogens, including, among others, HSV-1, CMV, C. pneumoniae and spirochetes (Refs Reference Lang255, Reference Hook256, Reference Comandini257, Reference Tobian and Quinn258).

Correlates of infection risk and AD

Based on the data available on the association of spirochetes, C. pneumoniae and HSV-1 with AD, contingency tables were used to analyse the strength of the association and the risk of infection in AD. In those studies where all types of spirochetes were detected using neutral techniques, spirochetes were observed in the brain in 90.1% (64/71) of AD cases and were absent in controls without any AD-type changes. This difference is significant (Table 1), and the association remains significant when cases where spirochetes were analysed in the blood are also included. The association between periodontal pathogen spirochetes and AD is also statistically significant. They were detected in the brain in 93.7% of AD cases and in 33.3% of controls. B. burgdorferi was about 13 times more frequent in AD cases than in controls, a statistically significant difference. It is noteworthy that B. burgdorferi was detected in all AD cases with a positive serology or where spirochetes were cultivated from the brain (Table 1). Taken together, in all studies where spirochetes or their specific species (periodontal Treponema spirochetes or B. burgdorferi) were detected in the brain, it can be concluded that the frequency of spirochetes is more than eight times higher in AD cases (90/131; 68.7%) than in controls (6/71; 8.41%). That spirochetes were cultivated from the brains of AD patients indicates that viable spirochetes are present in advanced stages of dementia. They can sustain persisting infection and inflammation and cause neuronal destruction (Ref. Reference Miklossy148).

The frequency of C. pneumoniae was about five times higher in AD cases (60/125; 48%) than in controls (5/52; 9.6%). The difference remains significant when those cases where C. pneumoniae was detected in the CSF were also included (Table 1). That C. pneumoniae was cultivated from the brain (Refs Reference Gérard200, Reference Arking213) and CSF (Ref. Reference Paradowski202) and that replicative RBs were present in glial cells, neurons and pericytes in AD indicate that this microorganism is also present in a viable, active form in the brain in AD.

There is no significant difference between the frequency of HSV-1 detected in the brain in AD patients compared with age-matched control. However, a significant difference was observed between APOE ɛ4-positive and -negative AD carriers, as reported by several authors (Refs Reference Itzhaki236, Reference Itabashi237, Reference Lin238, Reference Burgos259, Reference Miller and Federoff260), except for Beffert and colleagues (Refs Reference Beffert239, Reference Beffert240). A significant association of AD with ongoing or reactivated HSV-1 infection was reported (Ref. Reference Letenneur245).

Evidence for a causal role of pathogens in AD

Additional studies have brought further evidence in favour of a probable causal relationship between spirochetes, C. pneumoniae, HSV-1 and AD. Exposure of primary mammalian neuronal and glial cells to spirochetes, namely to B. burgdorferi, which can be cultivated and propagated in pure culture, generated thioflavin-S-positive and Aβ-immunoreactive amyloid plaques and tangle- and granulovacuolar-like formations in vitro (Refs Reference Miklossy175, Reference Miklossy261). In situ, in the spirochete-induced Aβ plaques, synchrotron infrared microspectroscopy analysis revealed the presence of a β-pleated sheet conformation (Ref. Reference Miklossy261). Spirochete-induced increases in Aβ, APP and phosphorylated tau were all detected by western blot in infected cell cultures (Ref. Reference Miklossy261). This additional experimental evidence indicates that spirochetes are able to induce an AD-type host reaction and reproduce the defining pathological and biological hallmarks of AD (Refs Reference Miklossy175, Reference Miklossy261). Similar in vitro studies performed on CNS organotypic cultures, which aim to replace in vivo experiments, showed identical results (Ref. Reference Miklossy261). Reference B. burgdorferi spirochetes (strain B31) and those cultivated from the AD brain (strains ADB1 and ADB2) invaded neurons and glial cells and induced nuclear fragmentation in vitro, indicating that the spirochetes cultivated from the brains of AD patients are invasive and cause neuronal and glial damage and apoptosis (Refs Reference Miklossy175, Reference Miklossy261). Spirochetes occur in both extra- and intracellular locations. They invade neurons in vitro, in primary neuronal cultures (Refs Reference Miklossy175, Reference Miklossy261), in the cerebral cortex and in the trigeminal ganglia of AD patients (Refs Reference Miklossy146, Reference Riviere, Riviere and Smith147, Reference Miklossy148, Reference Miklossy149, Reference Miklossy175, Reference MacDonald183, Reference MacDonald184, Reference Miklossy261). Historical observations and illustrations showing that chronic spirochetal infection can reproduce the clinical, pathological and biological hallmarks of AD strongly support a causal relationship between spirochetal infection and AD (Refs Reference Pacheco e Silva114, Reference Pacheco e Silva115, Reference Miklossy, Rosemberg and McGeer124). All these observations indicate that various types of spirochetes, including B. burgdorferi and several periodontal pathogen spirochetes, in an analogous way to T. pallidum, can cause dementia, cortical atrophy and the pathological and biological hallmarks of AD.

Astrocytes and microglia infected in vitro with C. pneumoniae display inclusions that are indistinguishable from those characteristic of active infection of the standard HEp-2 host cell line (Refs Reference Dreses-Werringloer214, Reference Dreses-Werringloer215). It was reported that chronic or persistent infection of CNS cells with C. pneumoniae can affect apoptosis in AD, in both a pro- and antiapoptotic manner (Refs Reference Appelt203, Reference Dreses-Werringloer214, Reference Dreses-Werringloer215). Furthermore, infection of BALB/c mice by intranasal inhalation of C. pneumoniae initiated Aβ1–42 deposits in the brain that resembled senile plaques (Ref. Reference Little262). Antibiotic treatment following C. pneumoniae infection limited the number of induced amyloid plaques in vivo (Ref. Reference Hammond, Igbal, Winblat and Avila263).

The glycoprotein B (gB) of HSV-1 has a highly homologous sequence to a fragment of Aβ (Ref. Reference Cribbs264). Synthetic peptides derived from this region accelerate fibrillar aggregation of Aβ in vitro. They can self-assemble into fibrils, which are ultrastructurally indistinguishable from Aβ and are neurotoxic at a similar dose to Aβ. It was proposed that HSV-1 might act as a ‘seed’ for senile plaque formation (Ref. Reference Satpute-Krishnan, DeGiorgis and Bearer265). It was also shown that HSV-1 is associated with APP during its anterograde transport, which might affect APP degradation and synaptic function (Ref. Reference Satpute-Krishnan, DeGiorgis and Bearer265).

Exposure of cultured cells to HSV-1 results in increased intracellular Aβ levels in neurons and glial cells as analysed by immunocytochemistry, ELISA and western blot. Tau phosphorylation was also observed at a number of sites that are phosphorylated in AD (Refs Reference Wozniak266, Reference Zambrano267, Reference Wozniak, Frost and Itzhaki268). It was suggested that the association of viral DNA and senile plaques is very likely to be causal, because HSV-1 is able to increase the level of Aβ in neurons of infected mice in vivo (Ref. Reference Wozniak266).

Evidence for underlying mechanisms

Sources and dissemination

Spirochetes, C. pneumoniae and HSV-1 are all able to invade the brain (Fig. 3) and generate latent and persistent chronic infection (Refs Reference Balin144, Reference Balin145, Reference Miklossy146, Reference Riviere, Riviere and Smith147, Reference Miklossy148, Reference Miklossy149, Reference Jamieson228, Reference Bertrand229, Reference Leinonen269). The strong neurotropism of spirochetes is well known (Ref. Reference Gastinel167). In addition to haematogenous dissemination, spirochetes can spread through the lymphatic system and along nerve fibre tracts (Ref. Reference Gastinel167). Periodontal invasive spirochetes were detected in the trigeminal ganglia and along the trigeminal nerve (Ref. Reference Riviere, Riviere and Smith147). They might also propagate along the fila olfactoria and tractus olfactorius, which would enable them to reach the CSF, the septal and hippocampal regions in the earliest stages of the disease. This would be in harmony with the olfactory hypothesis (Refs Reference Averback94, Reference Mann, Tucker and Yates95, Reference Hardy96) and the early involvement of the olfactory tract and bulb (Ref. Reference Christen-Zaech97).

Figure 3. Sources and dissemination of pathogens associated with Alzheimer disease.

Through infected circulating monocytes, C. pneumoniae can also spread by haematogenous dissemination and, by crossing the blood–brain barrier, infect the brain. C. pneumoniae is an upper respiratory tract pathogen and can reach the brain through the olfactory system (Ref. Reference Mann, Tucker and Yates95). Intranasal inhalation of C. pneumoniae initiated plaque-like Aβ1–42 deposits in the brain in BALB/c mice, and C. pneumoniae-specific DNA was detected by PCR in the olfactory bulb in AD (Ref. Reference Little262).

HSV-1 infection might also reach the brain through the olfactory system, by infection of cranial and peripheral nerves and their ganglia and through haematogenous dissemination (Refs Reference Boggian270, Reference Valyi-Nagy271). The virus can reside in the brain in a latent form and be reactivated by peripheral infection, stress or immunosuppression (Ref. Reference Wozniak, Frost and Itzhaki268).

Neuroinflammation and TLR signalling

Persisting, poorly degradable bacterial remnants in mammalian tissues act as chronic inflammatory stimuli (Refs Reference Fox272, Reference Stimpson273, Reference Fleming, Wallsmith and Rosenthal274). Lipopolysaccharides (LPSs), PGN and various bacterial lipoproteins elicit a variety of proinflammatory responses and might represent an important source of inflammation in AD. Complex interactions between the innate and adaptive immune systems have a major role in infection (Ref. Reference Palaniyar275). The functions of innate immunity allow host cells to recognise most microorganisms, execute proinflammatory defences and start adaptive immune responses.

Bacteria attach to host cells through a variety of cell-surface components, including surface amyloid proteins, which interact with host proteases (Refs Reference Gebbink276, Reference Hammer277, Reference Gophna278, Reference Ben Nasr279, Reference Olsén, Jonsson and Normark280, Reference Sjöbring, Pohl and Olsén281, Reference Hammar282, Reference Umemoto, Li and Namikawa283). Proteolysis of the extracellular matrix allows bacteria to penetrate the basement membrane and invade host cells.

It is the innate immune system that provides the first line of defence against microorganisms. Pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), recognise unique structures of invading microorganisms (Ref. Reference Crack and Bray284). Patients with genetic defects related to signalling pathways activated by TLRs frequently suffer from severe recurrent infection (Refs Reference Lorenz285, Reference Kiechl, Wiedermann and Willeit286, Reference Akira and Takeda287, Reference Tobias and Curtiss288, Reference Turvey and Hawn289). In the absence of TLRs, death from experimental sepsis is significantly enhanced (Ref. Reference Akira and Takeda287). Various bacteria, including spirochetes, activate TLR signalling and interact with CD14 (Refs Reference Bulut290, Reference Sellati291, Reference Schroeder292). T. pallidum and B. burgdorferi or their synthetic membrane lipoproteins are major inflammatory mediators (Refs Reference Radolf293, Reference Ramesh294) and activate both the classical and alternative complement pathways, which opsonise and kill pathogens without the need for antibody.

Complex interactions between pathogen-associated molecular patterns (PAMPs), PRRs and TLR signalling pathways have a major role in linking innate and adaptive immunity and maintaining pathogen-free host tissues (Ref. Reference Palaniyar275). TLRs activate two major signalling pathways (Fig. 4). The core pathway activated by most TLRs leads to the activation of transcription factor nuclear factor-kappa B (NF-κB) and the mitogen-activated protein kinases (MAPKs) p38 and Jun kinase (JNK). The second pathway is activated by TLR3 and TLR4 and results in the activation of both NF-κB and interferon regulatory factor-3 (IRF3), allowing the induction of another set of inflammatory genes, including the antiviral interferon-β gene (IFNB).

Figure 4. Schematic representation of signalling pathways implicated in host–pathogen interactions in Alzheimer disease. Pattern recognition receptors (PRRs) recognise conserved structural components of microorganisms, called pathogen-associated molecular patterns (PAMPs) or ligands, which include peptidoglycan (PGN), lipoteichoic acid (LTA), flagellin (FLA), bacterial lipoprotein (BLP) and nucleic acid structures, such as bacterial CpG DNA or viral RNA, unique to bacteria and viruses. Lipopolysaccharide (LPS) is recognised following its binding to lipoprotein binding protein (LBP). Only Toll-like receptors (TLRs) have a cytoplasmic domain for signal transduction. Plasma-membrane-localised TLRs include TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10, whereas endosomal TLRs include TLR3, TLR7, TLR8 and TLR9. TLR9 is responsible for the recognition of CpG islands of bacterial DNA. Complex interactions between pathogen-associated molecular patterns (PAMPs), pattern recognition receptors (PRRs) and TLR signalling pathways have a major role in linking innate and adaptive immunity and maintaining pathogen-free host tissues. Mammals use antimicrobial peptides (AMPs) as part of their innate immune defences to destroy invading pathogens. In contrast, in a similar way, pore-forming bacterial surface proteins are also able to destroy host cells. Evasion of pathogens from destruction by the host immune defences will result in chronic persistent infection and host cell destruction. APP, amyloid precursor protein; Aβ, amyloid beta; CD14, cluster of differentiation 14; NF-κB, nuclear factor-kappa B; MALP2, mycoplasma diacylated lipopeptide 2; p38 MAPK, mitogen-activated protein kinase; JNK, c-Jun kinase; MAC, membrane attack complex; MD2, lymphocyte antigen 96; Akt, serine/threonine protein kinase Akt1; IRF, interferon regulatory factor; IL, interleukin; TNF, tumour necrosis factor; COX2, cyclooxygenase 2; IFN, interferon, CREB, cAMP response element binding.

Activation of p38 MAPKs during bacterial infection was also shown to be crucial in the local production of cytokines such as IL-8 (Ref. Reference Ratner295) and in the development of effective immune responses in vivo (Ref. Reference van den Blink296). Toxin-induced p38 MAPK activation requires pore formation and is inhibited by the relief of osmotic stress.

Pore-forming toxins are the most common class of bacterial protein toxins and are often important virulence factors (Ref. Reference Van der Goot297). Pore-forming bacterial toxins are typically oligomers of soluble, monomeric proteins or peptides, which form transmembrane channels. Channel formation in the membrane of targeted cells, which triggers cellular ion imbalance, is a widely used form of bacterial attack (Refs Reference Gekara298, Reference Gonzalez299). These pore-forming bacterial toxins generate calcium-dependent and lipid-mediated signalling on host cell surfaces, leading to a variety of events such as tyrosine phosphorylation (Ref. Reference Gekara and Weiss300), actin rearrangement (Ref. Reference Cossart and Lecuit301), NF-κB activation (Ref. Reference Kayal302) and regulation of gene expression through histone modification (Ref. Reference Hamon303).

Mammals also use bacterial porin-like proteins such as perforins as part of their innate immune defences (Ref. Reference Pipkin and Lieberman304). Aβ1–42 was shown to be an AMP that belongs to the innate immune system. Toxic oligomers of Aβ1–42 bind to lipid bilayers of bacterial membranes and enveloped viruses, triggering Ca2+ influx and bacteriolysis or viral destruction. Deregulation of the balance between host cell destruction by pathogens and pathogen destruction by the host immune systems will influence the outcome of infections.

The innate and alternative pathways through the common membrane attack complex (MAC, C5b9) cause bacteriolysis (Refs Reference Blanco305, Reference Lawrenz306, Reference Kraiczy307). Cellular and humoral components of the immune system reactions are both associated with AD (Refs Reference McGeer98, Reference Griffin99, Reference McGeer and Rogers100, Reference Schwab and McGeer101, Reference McGeer and McGeer102). The adaptive immune system kills pathogens through the formation of specific antibodies directed against invading microorganisms. Monocytes, macrophages and microglia participate in both the innate and adaptive immune responses. When activated, they secrete chemokines and cytokines and express various proinflammatory molecules needed for the efficient removal of pathogens and damaged cells.

Neuroinflammatory responses that include activation of glia with marked elevation of cytokine expression, in particular elevation of IL-1, are observed in AD, in Down syndrome fetuses and children before plaque formation, and also in HIV infection (Refs Reference Griffin99, Reference Stanley308, Reference Brabers and Nottet309). IL-1 directs both the in vivo (Ref. Reference Sheng310) and in vitro synthesis of APP (Ref. Reference Goldgaber311), thus favouring senile plaque formation in AD. IL-1 upregulation of ApoE promotes ApoE-mediated induction of APP (Ref. Reference Barger312) and MAPK-p38-mediated tau phosphorylation, in part by upregulation of MAPK-p38 synthesis and activation and by favouring the formation of neurofibrillary tangles (Refs Reference Li313, Reference Sheng314, Reference Sheng315). IL-1 also influences neurotransmission because it increases the synthesis and activation of AChE (Ref. Reference Li316) and induces neuron loss by increasing caspase 1 (IL-1β cleavage enzyme) activity (Refs Reference Zhu317, Reference Li318). Microglial activation by APP and release of secreted APP (sAPP) modulated by apolipoprotein E also have an important role in the degenerative process of AD (Refs Reference Li313, Reference Barger and Harmon319). Activation of microglia with TLR2, TLR4 and TLR9 ligands increases Aβ ingestion in vitro (Ref. Reference Tahara320). Furthermore, stimulation of the immune system through TLR9 in APP transgenic (Tg2576) mice reduces Aβ deposition (Ref. Reference Scholtzova321).

Evasion and establishment of latent and chronic infection

The ability of spirochetes and C. pneumoniae to evade destruction by host immune systems and establish chronic infection is well known. HSV-1 can also remain in a latent state and persist throughout life in human tissues. In the latent state, the viral genome is present, but no viral particles are produced. Viral gene expression during latency is limited to one locus – the gene encoding the latency-associated transcript (Ref. Reference Itzhaki and Wozniak151).

Pathogens use a broad range of strategies to overcome antigenic recognition, complement lysis and phagocytosis. Blockade of the complement cascade or acquisition of host-derived complement inhibitors results in their evasion from complement lysis. This allows microbial survival and proliferation even in immune-competent hosts. Complement-resistant strains of B. burgdorferi possess five complement regulatory acquiring surface proteins, which bind host complement inhibitors (Refs Reference Kraiczy307, Reference Kraiczy and Würzner322) and a CD59-like molecule (Refs Reference Kraiczy and Würzner322, Reference Pausa323). A fragment of HSV-1 glycoprotein C (gC) shares sequence similarity with host complement receptor 1 (CR1), showing that viruses can also escape from attack by the MAC. Bacteria and viruses protect themselves from destruction by the host adaptive immune system. B. burgdorferi induces IL-12, a cytokine recently recognised to be critical for driving cellular responses towards the Th1 subset of T helper cells (Refs Reference Radolf293, Reference Rasley, Anguita and Marriott324). This shift retards antibody induction by Th2 cells against bacteria. These various ways of evasion allow bacteria to survive and proliferate in host tissues and sustain chronic infection.

Iron and nitric oxide

Bacterial cell wall components, including LPSs and PGNs, are highly resistant to degradation by mammalian enzymes and persist indefinitely in mammalian tissues. During chronic exposure, bacteria and bacterial debris accumulate in infected host tissues, sustaining chronic inflammation and slowly progressive cell damage (Refs Reference Fox272, Reference Stimpson273, Reference Fleming, Wallsmith and Rosenthal274, Reference Hauss-Wegrzyniak, Vraniak and Wenk325, Reference Lehman326). Bacteria, LPSs and PGNs have a variety of biological actions in mammals (Ref. Reference Johannsen327). They not only are inflammatory cytokine inducers and activators of complement pathways, but they also affect vascular permeability (Ref. Reference Schwab328), induce nitric oxide and free radicals, inhibit DNA synthesis, and cause apoptosis and cellular damage (Ref. Reference Heiss329).

Macrophage regulation of immune surveillance involves iron depletion (Refs Reference Weinberg and Miklossy330, Reference Griffiths331, Reference Weinberg332). Lactoferrin, which is similar in structure to transferrin, has a role in natural defence mechanisms in mammals and is upregulated in neurodegenerative disorders. Lactoferrin exerts its anti-inflammatory action by inhibiting hydroxyl radical formation. This antioxidant property prevents DNA damage (Ref. Reference Heiss329). By contrast, free iron abolishes the bactericidal effects of serum and strongly enhances infection and bacterial virulence (Refs Reference Heiss329, Reference Weinberg and Miklossy330, Reference Griffiths331, Reference Weinberg332). Iron has been shown to increase the formation of reactive oxygen intermediates, resulting in lipid peroxidation and subsequent oxidative damage of proteins and nucleic acids (Refs Reference Weinberg and Miklossy330, Reference Griffiths331, Reference Weinberg332). By affecting T-cell generation, iron also influences antigen-specific cellular responses, T-cell functions and the production of proinflammatory cytokines by macrophages (Ref. Reference Griffiths333). Iron, which has a fundamental role in infection, also accumulates in senile plaques in AD (Refs Reference Weinberg and Miklossy330, Reference Goodman334, Reference Bishop335, Reference Miller336).

Activation of macrophages and other host cells by bacteria or LPS causes inducible nitric oxide synthase (iNOS) synthesis, which in turn generates substantial amounts of nitric oxide from the amino acid l-arginine (Ref. Reference Weinberg332). Nitric oxide is a critical component in the clearance of bacterial, viral, fungal and parasitic infections (Ref. Reference Lirk, Hoffmann and Rieder337). In a mouse model, genetic disruption of iNOS was associated with a significantly higher risk of dissemination and mortality of infection (Ref. Reference Chan, Chan and Schluger338). Pathogens have also evolved a broad array of strategies to limit nitric oxide production (Refs Reference Chan, Chan and Schluger338, Reference Chakravortty and Hensel339, Reference Shiloh and Nathan340), which might contribute to their evasion from host immune responses (Ref. Reference Shiloh and Nathan340). Nitric oxide also has a central role in chronic degenerative diseases, including AD (Ref. Reference Bogdan341).

Amyloidogenesis

Amyloidogenesis is the aggregation of soluble proteins into detergent-insoluble filamentous structures about 10 nm wide and 0.1–10 µm long. These amyloid fibrils have distinct biochemical and biophysical properties, including resistance to proteinase K treatment, β-sheet structure and affinity for binding thioflavin S and Congo Red.

Chronic bacterial infections (e.g. rheumatoid arthritis, leprosy, tuberculosis, syphilis, osteomyelitis) are frequently associated with amyloid deposition. Cortical and vascular amyloid deposition in the atrophic form of general paresis, caused by a spirochete (T. pallidum), as in AD, corresponds to Aβ.

On the basis of previous observations, it has been suggested that amyloidogenic proteins might be an integral part of spirochetes and can contribute to Aβ deposition in AD (Ref. Reference Miklossy146). It was shown that the BH(Reference Terry9Reference Kang10) peptide on a β-hairpin segment of B. burgdorferi OspA forms amyloid fibrils in vitro that are similar to those in human amyloidosis (Ref. Reference Ohnishi, Koide and Koide342). Recent observations indicate that amyloid proteins constitute a previously overlooked integral part of the cellular envelope of many bacteria (Refs Reference Otzen and Nielsen343, Reference Chapman344, Reference Larsen345, Reference Jordal346). Amyloid fibril formation not only results in toxic aggregates, but also provides biologically functional molecules (Refs Reference Otzen and Nielsen343, Reference Chapman344, Reference Wang, Hammer and Chapman347). Bacterial amyloids are involved in bacterial cell–cell interactions, in their attachment to inert solid surfaces, and in spore and biofilm formation (Ref. Reference Wang, Hammer and Chapman347). Microbial amyloids, through interaction with host proteases, also contribute to bacterial virulence, to colonisation of the host and to invasion of host cells.

Bacterial LPSs and PGNs are used worldwide to generate in vitro and in vivo experimental inflammation and amyloidosis (Ref. Reference Picken348). LPSs induce Aβ accumulation, increased APP levels and hyperphosphorylation of tau in vitro and in vivo (Refs Reference Miklossy261, Reference Hauss-Wegrzyniak and Wenk349, Reference Miklossy350, Reference Kitazawa351). Increased APP mRNA in response to LPS was also detected in the basal forebrain and hippocampus of the rat (Ref. Reference Hauss-Wegrzyniak and Wenk349). Aβ deposition occurs in the brains of rats chronically infused with LPSs (Ref. Reference Hauss-Wegrzyniak and Wenk349). In a triple-transgenic mouse model of AD, repeated challenges with LPSs were shown to exacerbate CNS inflammation and to cause increased tau phosphorylation (Ref. Reference Kitazawa351).

Genetic factors

Host responses to bacterial infections are genetically controlled. Promoter polymorphisms in the genes of proinflammatory cytokines are associated with susceptibility to infection (Ref. Reference Knight and Kwiatkowski352). Tumour necrosis factor alpha (TNF-α) is a critical mediator of host defence against infection. Polymorphisms in the gene encoding TNF-α might determine a strong cell-mediated immune response or a weak or absent cellular response, which reflects the genetic variability in cytokine production (Refs Reference Knight and Kwiatkowski352, Reference Shaw353). In the absence of cell-mediated immune responses, the microorganism can spread freely and accumulate in infected host tissues (Ref. Reference Roy354). Accordingly, in Mycobacterium leprae infection, two distinct phenotypes can be distinguished: tuberculoid leprosy and the lepromatous leprosy. In the tuberculoid or paucibacillary form, there is strong inflammatory infiltration and the number of microorganisms is low. Conversely, in the lepromatous or bacillary form, the inflammatory infiltrates are poor or absent and the number of M. leprae is high. A similar polarity in host reactions – the infiltrative form with strong cell-mediated immune responses and few spirochetes versus the atrophic form, lacking lymphoplasmocytic infiltrates but with numerous spirochetes – occurs in response to T. pallidum and B. burgdorferi infection (Refs Reference Pacheco e Silva114, Reference Pacheco e Silva115, Reference Miklossy, Duyckaerts and Litvan118, Reference Miklossy149). The influence of TNF-α polymorphism on spirochetal infections has also been demonstrated by others (Refs Reference Marangoni355).

Class II major histocompatibility genes influence host immune responses to bacterial and viral infections. The major histocompatibility complex phenotype of the antigen-presenting cell can modulate Th1-like versus Th2-like cell activity against M. leprae and other pathogens. In general, it has been acknowledged that human leukocyte antigen (HLA) DR isotypes are associated with a protective response, whereas DQ isotypes are associated with the multibacillary lepromatous form with a limited cellular response. HLA gene polymorphism is a dominant marker of susceptibility to various infections, including B. burgdorferi infection (Ref. Reference Steere, Dwyer and Winchester356). The important role of the HLA system in controlling cell-mediated responses suggests that differences in HLA haplotypes could contribute to the wide spectrum of immune responses observed in leprosy and in other infections (Ref. Reference Lagrange and Abel357). It is noteworthy that TNF-α and HLA polymorphisms, which are risk factors for infection, substantially influence the risk of AD (Refs Reference McGeer and McGeer61, Reference Collins358, Reference McCusker359, Reference Gnjec360, Reference Alves361, Reference Ballerini362).

Association between AD pathology and IL-1β expression patterns (Ref. Reference Griffin363), and between disease risk and IL-1β gene polymorphisms, has been reported (Refs Reference Bertram62, Reference Nicoll364). Genetic variation in the expression of microbial PRRs, including TLRs, and CD14 gene polymorphisms predispose to various infections and are also associated with AD (Refs Reference Minoretti365, Reference Balistreri366).

Genetic mutations in APP, PS1 and PS2 are related to the processing of APP (Ref. Reference Hardy39). Because APP has an important role in the regulation of immune system reactions and in T-cell differentiation (Refs Reference Allen16, Reference Mönning17, Reference Ledoux18), genetic defects in such genes should also result in increased susceptibility to infection.

APOE ɛ4 enhances the expression of inflammatory mediators (Refs Reference Urosevic and Martins367, Reference Licastro368) and has a modulatory function in susceptibility to infection by various bacteria, viruses and protozoa (Refs Reference Urosevic and Martins367, Reference Licastro368, Reference Corder369, Reference Itzhaki370, Reference Itzhaki and Wozniak371, Reference Bhattacharjee372). APOE genotyping of three AD cases, where B. burgdorferi was detected and cultivated from the brain, showed that two of them were APOE ɛ4 carriers. The low number of cases does not allow any conclusion for an eventual link between spirochetal infection and the APOE ɛ4 allele (Ref. Reference Miklossy149). Sixty-four per cent of AD cases with positive C. pneumoniae PCR had at least one APOE ɛ4 allele (Ref. Reference Hudson and Dolmer207). ISH and quantitative real-time PCR analyses indicated that the number of C. pneumoniae-infected cells and the bacterial load in affected brain regions of APOE ɛ4 carriers in AD were significantly higher compared with those lacking that allele (Ref. Reference Gérard200). Furthermore, HIV-1-infected subjects carrying the APOE ɛ4 allele have higher recorded levels of dementia (Ref. Reference Corder369), and the ɛ4 allele has also been shown to modulate HSV-1 infection (Refs Reference Beffert240, Reference Burgos259, Reference Miller and Federoff260, Reference Itzhaki and Wozniak371).

Outstanding research questions and conclusions

The analysis of all positive and negative data available in the literature on the association of pathogens with AD indicates a statistically significant association between various types of spirochetes, C. pneumoniae and AD. There is no significant difference between the frequency of HSV-1 in AD cases compared with age-matched controls. However, several authors found a significant difference between the frequencies of HSV-1 in APOE ɛ4 carriers and noncarriers. The occurrence of positive anti-HSV-1 IgM was reported to be a risk factor for AD (for a recent review, see Ref. Reference Itzhaki and Wozniak373).

Lesions that are similar to senile plaques, neurofibrillary tangles and neuropil threads, and granulovacuolar degeneration, accumulation of Aβ, increased APP levels and phosphorylation of tau have all been induced by exposure of mammalian neuronal and glial cells and CNS organotypic cultures to spirochetes. Aβ-positive plaques were induced by inhalation of C. pneumoniae in mice in vivo, and exposure to HSV-1 increased the Aβ level and produced tau phosphorylation in neurons in vitro and in vivo.

Through TLRs and other PRRs, pathogens or their toxic components induce gene expression and activation of proinflammatory molecules by host cells. Both the classical and alternative complement pathways are activated in AD. MAC(C5b-9), which is intended to lyse bacteria or encapsulated viruses, and activated microglia that are designed to clean up debris and foreign bacteria are both associated with cortical AD lesions.

Evasion of pathogens from host defence reactions results in sustained infection and inflammation. The microorganisms and their toxic components can be observed in affected brains, along with host immunological responses.

Spirochetes, C. pneumoniae and HSV-1 disseminate from the primary site of infection to the brain usually through systemic infection. As in syphilis, systemic infection and inflammation precede the development of dementia by years or decades. Detection of infection in its early, peripheral stage can hamper its dissemination to the CNS and prevent dementia. Consequently, peripheral infections can have a role in the initiation and progression of neurodegeneration in AD (Refs Reference Miklossy146, Reference Perry, Cunningham and Holmes374, Reference Perry, Nicoll and Holmes375, Reference Holmes and Cotterell376). Worsening of peripheral and systemic infection will deteriorate CNS involvement. One example is periodontitis, which is caused mostly by Gram-negative bacteria, including periodontal spirochetes, which represents a risk factor for AD (Refs Reference Kamer156, Reference Kamer377).

It is important to consider that several types of spirochetes and several types of pathogens can occur in AD. Coinfection of B. burgdorferi with various periodontal spirochetes (Ref. Reference Riviere, Riviere and Smith147) or with T. pallidum (Ref. Reference Blatz378) is well documented. T. pallidum frequently coinfects with other bacteria and herpes viruses in syphilis (Ref. Reference Gastinel167). In Lyme disease, coinfection of B. burgdorferi with C. pneumoniae and HSV-1, which are also associated with AD, can be observed. Coinfection by several microorganisms can accelerate the degenerative process, exacerbate CNS damage and worsen dementia.

An infectious origin of AD is in harmony with recent observations showing that Aβ belongs to the group of AMPs, which are potent, broad-spectrum bactericides targeting Gram-negative and Gram-positive bacteria, enveloped viruses, fungi and protozoans (Ref. Reference Soscia31). Aβ has the capacity to associate with lipid bilayers of bacterial cell membranes and to exert antimicrobial activity by membrane permeabilisation and by alteration of calcium homeostasis (Refs Reference Soscia31, Reference Bolintineanu379). The microtubule-binding site of tau protein also exhibits antimicrobial properties (Ref. Reference Kobayashi380).

Inflammation has a primordial role in the elimination of invading pathogens and infected host cells. If infection is eradicated, it helps the healing process. Some proinflammatory molecules, such as cytokine IL-1β, in addition to their harmful effects, have a beneficial and protective effect (Ref. Reference Shaftel381). Therefore, long-term use of anti-inflammatory drugs alone might weaken the elimination of pathogens and facilitate their evasion, survival and slowly progressive proliferation. Combined antibiotic, antiviral and anti-inflammatory therapy is suggested as the treatment of choice.

In conclusion, the data available indicate that infectious agents can initiate the degenerative process in AD, sustain chronic inflammation, and lead to progressive neuronal damage and amyloid deposition. The accumulated knowledge, views and hypotheses proposed to explain the pathogenesis of AD fit well with an infectious origin of the disease. The outcome of infection is determined by the genetic predisposition of the patient, by the virulence and biology of the infecting agent, and by various environmental factors, such as exercise, stress and nutrition.

More attention and support is needed for this emerging field of research. Infection starts long before the manifestation of dementia; therefore, an adequate treatment should start early. Because antibacterial, antiviral and anti-inflammatory therapy is available, as in syphilis, one could prevent and eradicate dementia. The effect on the suffering of patients and on the reduction of healthcare costs would be considerable.

Acknowledgements and funding

I am grateful to all those colleagues and friends who strongly supported my work on this emerging field of research during the last two decades. They all contributed, in different ways, to the realisation of this work. I thank B. Balin, A. Hudson, J. Hudson and R. Itzhaki, who have reviewed and completed data related to their field of research on C. pneumoniae and HSV-1, and R. Kraftsik for his help with the statistical analysis. This work was funded by the Prevention Alzheimer International Foundation, Switzerland. I am grateful to the peer reviewers and to the editors of the journal, who significantly contributed with their constructive advice and remarks.

References

1Alzheimer, A. (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medicin 64, 146148Google Scholar
2Alzheimer, A. (1911) Über eigenartige Krankheitsfälle des späteren Alters. Zeitschrift für die gesamte Neurologie und Psychiatrie 4, 356385CrossRefGoogle Scholar
3Katzman, R. (1976) The prevalence and malignancy of Alzheimer's disease: a major killer. Archives of Neurology 33, 217218CrossRefGoogle ScholarPubMed
4Terry, R.D. and Davies, P. (1980) Dementia of the Alzheimer type. Annual Review of Neuroscience 3, 7795CrossRefGoogle ScholarPubMed
5Blocq, P. and Marinesco, G. (1892) Sur les lésions et la pathogénie de l'épilepsie dite essentielle. Semaine Médicale 12, 445446Google Scholar
6Redlich, E. (1898) Über miliare Sklerose der Hirnrinde bei seniler Atrophie. Jahrbuch für Psychiatrie und Neurologie 17, 208216Google Scholar
7Gallyas, F. (1971) Silver staining of Alzheimer's neurofibrillary changes by means of physical development. Acta Morpholpgica-Academiae Scientiarum Hungaricae 19, 18Google ScholarPubMed
8Simchowicz, T. (1911) Histologische Studien über die senile Demenz. Histologie Und Histopathologie Arb über Grosshirnrinde 4, 367444Google Scholar
9Terry, R.D. et al. (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Annals of Neurology 30, 572580CrossRefGoogle ScholarPubMed
10Kang, J. et al. (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733736CrossRefGoogle ScholarPubMed
11Selkoe, D.J. (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends in Cell Biology 8, 447453CrossRefGoogle ScholarPubMed
12Glenner, G.G. and Wong, C.W. (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysical Research Communications 120, 885890CrossRefGoogle ScholarPubMed
13Schubert, D. et al. (1988) Amyloid beta protein precursor is possibly a heparan sulfate proteoglycan core protein. Science 241, 17591763CrossRefGoogle ScholarPubMed
14Bush, A.I., Beyreuther, K. and Masters, C.L. (1993) The beta A4 amyloid protein precursor in human circulation. Annals of the New York Academy of Sciences 695, 175182CrossRefGoogle ScholarPubMed
15Li, Q.X. et al. (1999) The amyloid precursor protein of Alzheimer disease in human brain and blood 66, 567574Google ScholarPubMed
16Allen, J.S. et al. (1991) Alzheimer's disease: beta-amyloid precursor protein mRNA expression in mononuclear blood cells. Neuroscience Letters 132, 109112CrossRefGoogle ScholarPubMed
17Mönning, U. et al. (1990) Synthesis and secretion of Alzheimer amyloid beta A4 precursor protein by stimulated human peripheral blood leucocytes. FEBS Letters 277, 261266CrossRefGoogle ScholarPubMed
18Ledoux, S. et al. (1993) Amyloid precursor protein in peripheral mononuclear cells is up-regulated with cell activation. Journal of Immunology 150, 55665575CrossRefGoogle ScholarPubMed
19Jarrett, J.T. and Lansbury, P.T. (1992) Amyloid fibril formation requires a chemically discriminating nucleation event: studies of an amyloidogenic sequence from the bacterial protein OsmB. Biochemistry 31, 1234512352CrossRefGoogle ScholarPubMed
20Kim, W. and Hecht, M.H. (2005) Sequence determinants of enhanced amyloidogenicity of Alzheimer A{beta}42 peptide relative to A{beta}40. Journal of Biological Chemistry 280, 3506935076CrossRefGoogle Scholar
21Lambert, M.P. et al. (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences of the United States of America 95, 64486453CrossRefGoogle ScholarPubMed
22Hartley, D.M. et al. (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. Journal of Neuroscience 19, 88768884CrossRefGoogle ScholarPubMed
23Walsh, D.M. et al. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535539CrossRefGoogle ScholarPubMed
24Kirkitadze, M.D., Bitan, G. and Teplow, D.B. (2002) Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. Journal of Neuroscience Research 69, 567577CrossRefGoogle ScholarPubMed
25Cerf, E. et al. (2009) Antiparallel beta-sheet: a signature structure of the oligomeric amyloid beta- peptide. Biochemical Journal 421, 415423CrossRefGoogle ScholarPubMed
26Pitt, J. et al. (2009) Alzheimer's-associated Abeta oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal. Toxicology and Applied Pharmacology 240, 189197CrossRefGoogle ScholarPubMed
27Lashuel, H.A. et al. (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291CrossRefGoogle ScholarPubMed
28Rudel, T. et al. (1996) Modulation of Neisseria porin (PorB) by cytosolic ATP/GTP of target cells: parallels between pathogen accommodation and mitochondrial endosymbiosis. Cell 85, 391402CrossRefGoogle ScholarPubMed
29Ayala, P. et al. (2005) The pilus and porin of Neisseria gonorrhoeae cooperatively induce Ca(2+) transients in infected epithelial cells. Cellular Microbiology 7, 17361748CrossRefGoogle ScholarPubMed
30Müller, A. et al. (1999) Neisserial porin (PorB) causes rapid calcium influx in target cells and induces apoptosis by the activation of cysteine proteases. EMBO Journal 18, 339352CrossRefGoogle ScholarPubMed
31Soscia, S.J. et al. (2010) The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 5, e9505CrossRefGoogle ScholarPubMed
32Kidd, M. (1963) Paired helical filaments in electron microscopy of Akzheimer's disease. Nature 197, 192193CrossRefGoogle ScholarPubMed
33Terry, R.D. (1963) The fine structure of neurofibrillary tangles in Alzheimer's disease. Journal of Neuropathology and Experimental Neurology 22, 629642CrossRefGoogle ScholarPubMed
34Goedert, M., Trojanowski, J.Q. and Lee, V.M.-Y. (1996) The neurofibrillary pathology of Alzheimer's disease. In The molecular and genetic basis of neurological disease. (2nd edn) (Rosenberg, R.N., et al. , eds), Butterworth-Heinemann, Stoneham, MA.Google Scholar
35Lee, V.M.-Y. (1995) Disruption of the cytoskeleton in Alzheimer's disease. Current Opinion in Neurobiology 5, 663668CrossRefGoogle ScholarPubMed
36Lu, P.J. et al. (1999) The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784788CrossRefGoogle ScholarPubMed
37Sherrington, R. et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754760CrossRefGoogle ScholarPubMed
38Selkoe, D.J. (1996) Amyloid beta-protein and the genetics of Alzheimer's disease. Journal of Biological Chemistry 271, 1829518298CrossRefGoogle ScholarPubMed
39Hardy, J. (1997) The Alzheimer family of diseases: many etiologies, one pathogenesis? Proceedings of the National Academy of Sciences of the United States of America 94, 20952097CrossRefGoogle ScholarPubMed
40Tanzi, R.E. and Bertram, L. (2001) New frontiers in Alzheimer's disease genetics. Neuron 32, 181184CrossRefGoogle ScholarPubMed
41Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353356CrossRefGoogle ScholarPubMed
42Bertram, L. and Tanzi, R.E. (2005) The genetic epidemiology of neurodegenerative disease. Journal of Clinical Investigation 115, 14491457CrossRefGoogle ScholarPubMed
43Nagy, Z. (2005) The last neuronal division: a unifying hypothesis for the pathogenesis of Alzheimer's disease. Journal of Cellular and Molecular Medicine 9, 531541CrossRefGoogle ScholarPubMed
44Schellenberg, G.D. (1995) Genetic dissection of Alzheimer disease, a heterogeneous disorder. Proceedings of the National Academy of Sciences of the United States of America 92, 85528559CrossRefGoogle ScholarPubMed
45Goate, A. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704706CrossRefGoogle ScholarPubMed
46Mullan, M. et al. (1992) A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nature Genetics 1, 345347CrossRefGoogle ScholarPubMed
47Alzheimer's Disease Collaborative Group (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer's Disease Collaborative Group. Nature Genetics 11, 219222Google Scholar
48Wasco, W. et al. (1995) Familial Alzheimer's chromosome 14 mutations. Nature Medicine 1, 848CrossRefGoogle ScholarPubMed
49Perez-Tur, J. et al. (1995) A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 7, 297301CrossRefGoogle ScholarPubMed
50Miklossy, J. et al. (2003) Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-on set Alzheimer's disease. Neurobiology of Aging 24, 655662CrossRefGoogle Scholar
51Levy-Lahad, E. et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973977CrossRefGoogle ScholarPubMed
52Citron, M. et al. (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360, 672674CrossRefGoogle ScholarPubMed
53Cai, X.D., Golde, T.E. and Younkin, S.G. (1993) Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259, 514516CrossRefGoogle ScholarPubMed
54Suzuki, N. et al. (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264, 13361340CrossRefGoogle ScholarPubMed
55Duff, K. et al. (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710713CrossRefGoogle ScholarPubMed
56Scheuner, D. et al. (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Medicine 2, 864870CrossRefGoogle ScholarPubMed
57Borchelt, D.R. et al. (1996) Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17, 10051013CrossRefGoogle ScholarPubMed
58Tomita, T. et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proceedings of the National Academy of Sciences of the United States of America 94, 20252030CrossRefGoogle ScholarPubMed
59Citron, M. et al. (1997) Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Medicine 3, 6772CrossRefGoogle ScholarPubMed
60Roses, A.D. (1994) Apolipoprotein E is a relevant susceptibility gene that affects the rate of expression of Alzheimer's disease. Neurobiology of Aging 2 (Suppl), 165167CrossRefGoogle Scholar
61McGeer, P.L. and McGeer, E.G. (2001) Polymorphisms in inflammatory genes and the risk of Alzheimer disease. Archives of Neurology 58, 17901792CrossRefGoogle ScholarPubMed
62Bertram, L. et al. (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature Genetics 39, 1723CrossRefGoogle ScholarPubMed
63Guo, J. et al. (2006) A-beta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 103, 19531958CrossRefGoogle Scholar
64Perry, G. et al. (1993) Immunocytochemical evidence that the beta-protein precursor is an integral component of neurofibrillary tangles of Alzheimer's disease. American Journal of Pathology 143, 15861593Google ScholarPubMed
65Davies, P., Katzman, R. and Terry, R.D. (1980) Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa. Nature 288, 279280CrossRefGoogle ScholarPubMed
66Perry, E.K. et al. (1981) Neurochemical activities in human temporal lobe related to aging and Alzheimer-type changes. Neurobiology of Aging 2, 251256CrossRefGoogle ScholarPubMed
67Rossor, M.N. (1982) Neurotransmitters and CNS disease. Dementia. Lancet 2, 12001204CrossRefGoogle ScholarPubMed
68Fowler, C.J. et al. (1992) Neurotransmitter, receptor and signal transduction disturbances in Alzheimer's disease. Acta Neurologica Scandinavica 139 (Suppl), 5962CrossRefGoogle ScholarPubMed
69Davies, P. and Maloney, A.J. (1976) Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2, 1403Google ScholarPubMed
70Bartus, R.T. et al. (1985) The cholinergic hypothesis: a historical overview, current perspective, and future directions. Annals of the New York Academy of Sciences 444, 332358CrossRefGoogle ScholarPubMed
71Martins, R.N. et al. (1986) Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer's disease may reflect oxidative stress. Journal of Neurochemistry 46, 10421045CrossRefGoogle ScholarPubMed
72Pappolla, M.A. et al. (1996) The heat shock/oxidative stress connection. Relevance to Alzheimer disease. Molecular and Chemical Neuropathology 28, 2134CrossRefGoogle ScholarPubMed
73Smith, M.A. et al. (1994) Advanced Maillard reaction end products, free radicals, and protein oxidation in Alzheimer's disease. Annals of the New York Academy of Sciences 738, 447454CrossRefGoogle ScholarPubMed
74Nunomura, A. et al. (2006) Involvement of oxidative stress in Alzheimer disease. Journal of Neuropathology and Experimental Neurology 65, 631641CrossRefGoogle ScholarPubMed
75Parker, W.D. Jr. (1991) Cytochrome oxidase deficiency in Alzheimer's disease. Annals of the New York Academy of Sciences 640, 5964CrossRefGoogle ScholarPubMed
76Terry, R.D. and Pena, C. (1965) Experimental production of neurofibrillary degeneration: electron microscopy, phosphatase histochemistry and electron probe analysis. Journal of Neuropathology and Experimental Neurology 24, 200210CrossRefGoogle ScholarPubMed
77Crapper, D.R., Krishnan, S.S. and Dalton, A.J. (1973) Brain aluminum distribution in Alzheimer's disease and experimental neurofibrillary degeneration. Science 180, 511513CrossRefGoogle ScholarPubMed
78Jellinger, K. et al. (1990) Brain iron and ferritin in Parkinson's and Alzheimer's diseases. Journal of Neural Transmission. Parkinson's Disease and Dementia Section 2, 327340CrossRefGoogle ScholarPubMed
79Suh, Y.H. et al. (1996) Molecular physiology, biochemistry, and pharmacology of Alzheimer's amyloid precursor protein (APP). Annals of the New York Academy of Sciences 786, 169183CrossRefGoogle Scholar
80Khachaturian, Z.S. (1994) Calcium hypothesis of Alzheimer's disease and brain aging. Annals of the New York Academy of Sciences 747, 111CrossRefGoogle ScholarPubMed
81Mori, H., Kondo, J. and Ihara, Y. (1987) Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235, 16411644CrossRefGoogle ScholarPubMed
82Lam, Y.A. et al. (2000) Inhibition of the ubiquitin-proteasome system in Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 97, 99029906CrossRefGoogle ScholarPubMed
83de la Torre, J.C. and Mussivand, T. (1993) Can disturbed brain microcirculation cause Alzheimer's disease? Neurological Research 15, 146153CrossRefGoogle ScholarPubMed
84Esiri, M.M. et al. (1999) Cerebrovascular disease and threshold for dementia in the early stage of Alzheimer's disease. Lancet 354, 919920CrossRefGoogle ScholarPubMed
85Hachinski, V. and Munoz, D.G. (1997) Cerebrovascular pathology in Alzheimer's disease: cause, effect or epiphenomenon? Annals of the New York Academy of Sciences 826, 16CrossRefGoogle ScholarPubMed
86Snowdon, D.A. et al. (1997) Brain infarction and the clinical expression of Alzheimer's disease. The Nun Study. Journal of the American Medical Association 277, 813817CrossRefGoogle ScholarPubMed
87De Jong, G.I. et al. (1997) Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies. Annals of the New York Academy of Sciences 826, 5674CrossRefGoogle ScholarPubMed
88Diaz, J.F. et al. (1991) Improved recognition of leukoaraiosis and cognitive impairment in Alzheimer's disease. Archives of Neurology 48, 10221025CrossRefGoogle ScholarPubMed
89Kalaria, R.N. (2000) The role of cerebral ischemia in Alzheimer's disease. Neurobiology of Aging 21, 321330CrossRefGoogle ScholarPubMed
90Suter, O.C. et al. (2002) Cerebral hypoperfusion generates cortical watershed microinfarcts in Alzheimer disease. Stroke 33, 19861992CrossRefGoogle ScholarPubMed
91Miklossy, J. (2003) Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's disease. Neurological Research 25, 605610CrossRefGoogle ScholarPubMed
92Muckle, T.J. and Roy, J.R. (1985) High-density lipoprotein cholesterol in differential diagnosis of senile dementia. Lancet 1, 11911193CrossRefGoogle ScholarPubMed
93Sparks, D.L. (1997) Coronary artery disease, hypertension, ApoE, and cholesterol: a link to Alzheimer's disease? Annals of the New York Academy of Sciences 826, 128146CrossRefGoogle ScholarPubMed
94Averback, P. (1983) Two new lesions in Alzheimer's disease. Lancet 2, 1203Google ScholarPubMed
95Mann, D.M., Tucker, C.M. and Yates, P.O. (1988) Alzheimer's disease: an olfactory connection? Mechanisms of Aging and Development 42, 115CrossRefGoogle ScholarPubMed
96Hardy, J.A. et al. (1986) An integrative hypothesis concerning the pathogenesis and progression of Alzheimer's disease. Neurobiology of Aging 7, 489502CrossRefGoogle ScholarPubMed
97Christen-Zaech, S. et al. (2003) Early olfactory involvement in Alzheimer's disease. Canadian Journal of Neurological Sciences 30, 2025CrossRefGoogle ScholarPubMed
98McGeer, P.L. et al. (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neuroscience Letters 79, 195200CrossRefGoogle ScholarPubMed
99Griffin, W.S. et al. (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 86, 76117615CrossRefGoogle ScholarPubMed
100McGeer, P.L. and Rogers, J. (1992) Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology 42, 447449CrossRefGoogle ScholarPubMed
101Schwab, C. and McGeer, P.L. (2008) Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. Journal of Alzheimer's Disease 13, 359369CrossRefGoogle ScholarPubMed
102McGeer, P.L. and McGeer, E.G. (1995) The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Research Reviews 21, 195218CrossRefGoogle ScholarPubMed
103McGeer, P.L. and McGeer, E.G. (2002) Local neuroinflammation and the progression of Alzheimer's disease. Journal of Neurovirology 8, 529538CrossRefGoogle ScholarPubMed
104Webster, S. et al. (1997) Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer's disease. Neurobiology of Aging 18, 415421CrossRefGoogle ScholarPubMed
105Stewart, W.F. et al. (1997) Risk of Alzheimer's disease and duration of NSAID use. Neurology 48, 626632CrossRefGoogle ScholarPubMed
106Zandi, P.P. et al. (2000) Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology 59, 880886CrossRefGoogle Scholar
107Veld, B.A.I. et al. (2000) Duration of non-steroidal antiinflammatory drug use and risk of Alzheimer's disease. The Rotterdam study. Neurobiology of Aging 21 (Suppl 1), S204Google Scholar
108Akiyama, H. et al. (2000) Inflammation and Alzheimer's disease. Neurobiology of Aging 21, 383421CrossRefGoogle ScholarPubMed
109Fischer, O. (1907) Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz. Monatsschrift für Psychiatrie und Neurologie 22, 361372CrossRefGoogle Scholar
110Wisniewsky, H.M. (1978) Possible viral etiology of neurofibrillary changes and neuritic plaques. In Alzheimer's Disease: Senile Dementia and Related Disorders (Aging, Vol. 7) (Katzman, R., Terry, R.D. and Bick, K.L., eds), pp. 555557, Raven Press, New York, NA.Google Scholar
111Khachaturian, Z.S. (1985) Diagnosis of Alzheimer's disease. Archives of Neurology 42, 10971105CrossRefGoogle ScholarPubMed
112Hübner, A.H. (1908) Zur Histopathologie der senilen Hirnrinde. Archives of Psychiatry and Neurology 46, 598609Google Scholar
113Perusini, G. (1910) Histology and clinical findings of some psychiatric diseases of older people. In Histologie und Histopathologische Arbeiten U die Grosshirnrhinde Vol. III (Nissl, F. and Alzheimer, A., eds), pp. 297–351, Gustav Fischer, Jena (Translated by Bick, K., Amaducci, L. and Pepeu, G.).Google Scholar
114Pacheco e Silva, A.C. (1926-27) Espirochetose dos centros nervos. Memorias do hospicio de Juquery, anno III-IV, 127Google Scholar
115Pacheco e Silva, A.C. (1926) Localisation du Treponema Pallidum dans le cerveau des paralytiques généraux. Revista de Neurologia 2, 558565Google Scholar
116Schlossberger, H. and Brandis, H. (1958). Ueber Spirochaeten-befunde in Zentralnervensystem mit besonderer Berucksichtigung der syphilogenen Erkrankungen. In Handbuch der Speziellen Pathologischen Anatomie und Histologie. Dreizehnter Band, Zweiter teil, Bandteil A, Erkrankungen des Zentralen Nervensystems II (Lubarsch, O., Henke, F. and Roessle, R., eds), pp. 10331172, Springer-Verlag, Berlin.Google Scholar
117Rizzo, C. (1931) Ricerche sulle spirochete nel cervello dei paralitici. Riv Pathol Nerv 37, 797814Google Scholar
118Miklossy, J. (2008) Biology and neuropathology of dementia in syphilis and Lyme disease. In Dementias, Handbook of Clinical Neurology (Duyckaerts, C. and Litvan, I., eds), Vol. 89, pp. 825844, Elsevier, Edinburgh, LondonGoogle Scholar
119Noguchi, H. and Moore, J.W. (1913) A demonstration of Treponema pallidum in the brain of general paralysis cases. Journal of Experimental Medicine 17, 232238CrossRefGoogle Scholar
120Merritt, H.H., Adams, R.D. and Solomon, H.C. (1946) Neurosyphilis, Oxford University Press, LondonGoogle Scholar
121Bonfiglio, F. (1908) Di speciali reperti in un caso di probabile sifilide cerebrale. Deutsche Pathologische Gesellschaft 34, 196206Google Scholar
122Vinken, P.J. and Bruyn, G.W. (1978) Handbook of Neurology, Vol. 33, Chapter 17, Elsevier, Amsterdam, New YorkGoogle Scholar
123Volland, W. (1938) Die Kolloide Degeneration des Gehirns bei progressiver Paralyse in ihrer Beziehung zur lokalen Amyloidose. Bulletins et mémoires de la Société médicale des hôpitaux de Paris 31, 515520Google Scholar
124Miklossy, J., Rosemberg, S. and McGeer, P.L. (2006). Beta amyloid deposition in the atrophic form of general paresis. In Alzheimer's Disease: New advances (Iqbal, K., Winblad, B. and Avila, J., eds), Medimond. International Proceedings. Proceedings of the 10th International Congress on Alzheimer's Disease (ICAD) 2006, pp. 429–433.CrossRefGoogle Scholar
125Marshall, B.J. and Warren, J.R. (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1, 13111315CrossRefGoogle ScholarPubMed
126Laitinen, K. et al. (1997) Chlamydia pneumonia infection induces inflammatory changes in the aortas of rabbits. Infection and Immunity 65, 48324835CrossRefGoogle ScholarPubMed
127Saikku, P. (1999) Epidemiology of Chlamydia pneumoniae in atherosclerosis. American Heart Journal 138 (Suppl), 500503CrossRefGoogle ScholarPubMed
128Mendall, M.A. et al. (1994) Relation of Helicobacter pylori infection and coronary heart disease. British Heart Journal 71, 437439CrossRefGoogle ScholarPubMed
129Martin de Argila, C. et al. (1995) High seroprevalence of Helicobacter pylori infection in coronary heart disease. Lancet 346, 310CrossRefGoogle ScholarPubMed
130Renvert, S. et al. (2006) Bacterial profile and burden of periodontal infection in subjects with a diagnosis of acute coronary syndrome. Journal of Periodontology 77, 11101119CrossRefGoogle ScholarPubMed
131Zaremba, M. et al. (2007) Evaluation of the incidence of periodontitis-associated bacteria in the atherosclerotic plaque of coronary blood vessels. Journal of Periodontology 78, 322327CrossRefGoogle ScholarPubMed
132Chiu, B. (1999) Multiple infections in carotid atherosclerotic plaques. American Heart Journal 138, S534S536CrossRefGoogle ScholarPubMed
133Haraszthy, V.I. et al. (2000) Identification of periodontal pathogens in atheromatous plaques. Journal of Periodontology 71, 15541560CrossRefGoogle ScholarPubMed
134Rassu, M. et al. (2001) Demonstration of Chlamydia pneumoniae in atherosclerotic arteries from various vascular regions. Atherosclerosis 158, 7379CrossRefGoogle ScholarPubMed
135Martin, R.J. (2006) Infections and asthma. Clinics in Chest Medicine 27, 8798CrossRefGoogle Scholar
136MacDowell, A.L. and Bacharier, L.B. (2005) Infectious triggers of asthma. Immunology and Allergy Clinics of North America 25, 4566CrossRefGoogle ScholarPubMed
137Micillo, E. et al. (2000) Respiratory infections and asthma. Allergy 61 (Suppl), 4245Google Scholar
138Marttila, R.J. et al. (1977) Viral antibodies in the sera from patients with Parkinson disease. European Neurology 15, 2533CrossRefGoogle ScholarPubMed
139Rott, R. et al. (1985) Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders. Science 228, 755756CrossRefGoogle ScholarPubMed
140Beaman, B.L. (1994). Bacteria and neurodegeneration. In Neurodegenerative Diseases (Caino, D., ed.), pp. 319338, W.B. Saunders, Orlando, FLGoogle Scholar
141Gosztonyi, G. and Ludwig, H. (1995) Borna disease-neuropathology and pathogenesis. Current Topics in Microbiology and Immunology 190, 3973Google ScholarPubMed
142Salvatore, M. et al. (1997) Borna disease virus in brains of North American and European people with schizophrenia and bipolar disorder. Lancet 349, 18131814CrossRefGoogle ScholarPubMed
143Langford, D. and Masliah, E. (2003) The emerging role of infectious pathogens in neurodegenerative diseases. Experimental Neurology 184, 553555CrossRefGoogle ScholarPubMed
144Balin, B.J. et al. (1998) Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Medical Microbiology and Immunology 187, 2342CrossRefGoogle ScholarPubMed
145Balin, B.J. et al. (2008) Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease. Journal of Alzheimer's Disease 13, 371380CrossRefGoogle ScholarPubMed
146Miklossy, J. (1993) Alzheimer's disease – a spirochetosis? Neuroreport 4, 841848CrossRefGoogle ScholarPubMed
147Riviere, G.R., Riviere, K.H. and Smith, K.S. (2002) Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer's disease. Oral Microbiology and Immunology 17, 113118CrossRefGoogle ScholarPubMed
148Miklossy, J. (2008) Chronic inflammation and amyloidogenesis in Alzheimer's disease – role of spirochetes. Journal of Alzheimer's Disease 13, 381391CrossRefGoogle ScholarPubMed
149Miklossy, J. et al. (2004) Borrelia burgdorferi persists in the brain in chronic Lyme neuroborreliosis and may be associated with Alzheimer disease. Journal of Alzheimer's Disease 6, 111Google ScholarPubMed
150Jamieson, G.A. et al. (1991) Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains. Journal of Medical Virology 33, 224227CrossRefGoogle ScholarPubMed
151Itzhaki, R.F. and Wozniak, M.A. (2008) Herpes simplex virus type 1 in Alzheimer's disease: the enemy within. Journal of Alzheimer's Disease 13, 393405CrossRefGoogle Scholar
152Olichney, J.M. et al. (2000) Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4. Archives of Neurology 57, 869874CrossRefGoogle Scholar
153Luchsinger, J.A. et al. (2005) Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65, 545551CrossRefGoogle Scholar
154Voisin, T. et al. (2003) Vascular risk factors and Alzheimer's disease. La Revue de Medecine Interne 24 (Suppl), 288291CrossRefGoogle ScholarPubMed
155Ott, A. et al. (1996) Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia 39, 13921397CrossRefGoogle Scholar
156Kamer, A.R. et al. (2008) Alzheimer's disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis. Journal of Alzheimer's Disease 13, 437449CrossRefGoogle ScholarPubMed
157Pihlstrom, B.L., Michalowicz, B.S. and Johnson, N.W. (2005) Periodontal diseases. Lancet 366, 18091820CrossRefGoogle ScholarPubMed
158Gibson, F.C. III et al. (2004) Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 109, 28012806CrossRefGoogle ScholarPubMed
159Mattila, K.J., Pussinen, P.J. and Paju, S. (2005) Dental infections and cardiovascular diseases: a review. Journal of Periodontology 76 (Suppl), 20852088CrossRefGoogle ScholarPubMed
160Seppaa, B. and Ainamo, J. (1996) Dark field microscopy of the subgingival microflora in insulin-dependent diabetics. Journal of Clinical Periodontology 23, 6367CrossRefGoogle ScholarPubMed
161Ling, L.J. et al. (2004) Association between human herpesviruses and the severity of periodontitis. Journal of Periodontology 75, 14791485CrossRefGoogle ScholarPubMed
162Heydenrijk, K. et al. (2002) Microbiota around root-form endosseous implants: a review of the literature. International Journal of Oral and Maxillofacial Implants 17, 829838Google ScholarPubMed
163O'Brien-Simpson, N.M. et al. (2004) Antigens of bacteria associated with periodontitis. Periodontology 2000 35, 101134CrossRefGoogle ScholarPubMed
164DeGraba, T.J. (2004) Immunogenetic susceptibility of atherosclerotic stroke: implications on current and future treatment of vascular inflammation. Stroke 35 (Suppl 1), 27122719CrossRefGoogle ScholarPubMed
165Kolb, H. and Mandrup-Poulsen, T. (2005) An immune origin of type 2 diabetes? Diabetologia 48, 10381050CrossRefGoogle ScholarPubMed
166Dewhirst, F.E. et al. (2000) The diversity of periodontal spirochetes by 16S rRNA analysis. Oral Microbiology and Immunology 15, 196202CrossRefGoogle ScholarPubMed
167Gastinel, P. (1949) Précis de bactériologie médicale. In Collections de précis médicaux. Masson and Cie, ParisGoogle Scholar
168Trott, D.J. et al. (1997) Identification and characterization of Serpulina pilosicoli isolates recovered from the blood of critically ill patients. Journal of Clinical Microbiology 35, 482485CrossRefGoogle ScholarPubMed
169Mikosza, A.S. et al. (2001) Comparative prevalences of Brachyspira aalborgi and Brachyspira (Serpulina) pilosicoli as etiologic agents of histologically identified intestinal spirochetosis in Australia. Journal of Clinical Microbiology 39, 347350CrossRefGoogle ScholarPubMed
170Burgdorfer, W. et al. (1982) Lyme disease-a tick-borne spirochetosis? Science 216, 13171319CrossRefGoogle ScholarPubMed
171Chan, E.C. et al. (1996) Characterization of a 4.2-kb plasmid isolated from periodontopathic spirochetes. Oral Microbiology and Immunology 11, 365368CrossRefGoogle Scholar
172Riviere, G.R. et al. (1991) Pathogen-related oral spirochetes from dental plaque are invasive. Infection and Immunity 59, 33773380CrossRefGoogle ScholarPubMed
173Peters, S. et al. (1999) Adherence to and penetration through cells by oral treponemes. Oral Microbiology and Immunology 14, 379383CrossRefGoogle ScholarPubMed
174Wyss, C. et al. (2004) Treponema putidum sp. nov., a medium-sized proteolytic spirochaete isolated from lesions of human periodontitis and acute necrotizing ulcerative gingivitis. International Journal of Systematic and Evolutionary Microbiology 54, 11171122CrossRefGoogle Scholar
175Miklossy, J. et al. (2008) Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. Journal of Neuroinflammation 5, 40CrossRefGoogle ScholarPubMed
176Miklossy, J. et al. (1995) Senile plaques, neurofibrillary tangles and neuropil threads contain DNA? Journal of Spirochetal and Tick-borne Diseases 2, 15Google Scholar
177Jacquet, L. and Sézary, A. (1907) Des formes atypiques et dégénératives du tréponéme pâle. Bull mem Soc Med Hop Par 24, 114Google Scholar
178MacDonald, A.B. and Miranda, J.M. (1987) Concurrent neocortical borreliosis and Alzheimer's disease. Human Pathology 18, 759761CrossRefGoogle ScholarPubMed
179Meer-Scherrer, L. et al. (2006) Lyme disease associated with Alzheimer's disease. Current Microbiology 52, 330332CrossRefGoogle ScholarPubMed
180Gutacker, M. et al. (1998) Arguments against the involvement of Borrelia burgdorferi sensu lato in Alzheimer's disease. Research in Microbiology 149, 3135CrossRefGoogle ScholarPubMed
181Marques, A.R. et al. (2000) Lack of evidence of Borrelia involvement in Alzheimer's disease. Journal of Infectious Diseases 182, 10061007CrossRefGoogle ScholarPubMed
182Galbussera, A. et al. (2008) Lack of evidence for Borrelia burgdorferi seropositivity in Alzheimer disease. Alzheimer Disease and Associated Disorder 22, 308CrossRefGoogle ScholarPubMed
183MacDonald, A.B. (2006) Transfection “Junk” DNA – a link to the pathogenesis of Alzheimer's disease? Medical Hypotheses 66, 11401141CrossRefGoogle Scholar
184MacDonald, A.B. (2006) Plaques of Alzheimer's disease originate from cysts of Borrelia burgdorferi, the Lyme disease spirochete. Medical Hypotheses. 67, 592600CrossRefGoogle ScholarPubMed
185Pappolla, M.A. et al. (1989) Concurrent neuroborreliosis and Alzheimer's disease: analysis of the evidence. Human Pathology 20, 753757CrossRefGoogle ScholarPubMed
186Miklossy, J. (1994) The spirochetal etiology of Alzheimer's disease: A putative therapeutic approach. In Alzheimer Disease: Therapeutic Strategies. Proceedings of the Third International Springfield Alzheimer Symposium (Giacobini, E. and Becker, R., eds), Part I, pp. 4148, Birkhauser, BostonCrossRefGoogle Scholar
187Miklossy, J. et al. (1994) Further morphological evidence for a spirochetal etiology of Alzheimer's Disease. NeuroReport 5, 12011204CrossRefGoogle Scholar
188Miklossy, J. et al. (1996) Bacterial peptidoglycan in neuritic plaques in Alzheimer's disease. Azheimer's Research 2, 95100Google Scholar
189Miklossy, J. (1998) Chronic inflammation and amyloidogenesis in Alzheimer's disease: Putative role of bacterial peptidoglycan, a potent inflammatory and amyloidogenic factor. Alzheimer's Reviews 3, 4551Google Scholar
190Hesse, L. et al. (2003) Functional and biochemical analysis of Chlamydia trachomatis MurC, an enzyme displaying UDP-N-acetylmuramate:amino acid ligase activity. Journal of Bacteriology 185, 65076512CrossRefGoogle ScholarPubMed
191McCoy, A.J. et al. (2006) L,L-diaminopimelate aminotransferase, a trans-kingdom enzyme shared by Chlamydia and plants for synthesis of diaminopimelate/lysine. Proceedings of the National Academy of Sciences of the United States of America 103, 1790917914CrossRefGoogle ScholarPubMed
192McLaughlin, R. et al. (1999) Alzheimer's disease may not be a spirochetosis. Neuroreport 10, 14891491CrossRefGoogle ScholarPubMed
193Mattman, L.H. (1993) Cell Wall Deficient Forms: Stealth Pathogens (2nd edn), CRC Press, Inc, Boca Raton, FL.Google Scholar
194MacDonald, A.B. (1986) Borrelia in the brains of patients dying with dementia. Journal of the American Medical Association 256, 21952196CrossRefGoogle ScholarPubMed
195Dupuis, M.J. (1988) Multiple neurologic manifestations of Borrelia burgdorferi infection. Revista de Neurologia 144, 765775Google ScholarPubMed
196Schaeffer, S. et al. (1994) Dementia in Lyme disease. Presse Medicale 23, 861Google ScholarPubMed
197Fallon, B.A. and Nields, J.A. (1994) Lyme disease: a neuropsychiatric illness. American Journal of Psychiatry 151, 1571–183Google ScholarPubMed
198Pennekamp, A. and Jaques, M. (1997) Chronic neuroborreliosis with gait ataxia and cognitive disorders. Praxis 86, 867869Google ScholarPubMed
199MacDonald, A.B. (1988) Concurrent neocortical borreliosis and Alzheimer's Disease. Annals of the New York Academy of Sciences 539, 468470CrossRefGoogle Scholar
200Gérard, H.C. et al. (2005) The load of Chlamydia pneumoniae in the Alzheimer's brain varies with APOE genotype. Microbial Pathogenesis 39, 1926CrossRefGoogle ScholarPubMed
201Gérard, H.C. et al. (2006) Chlamydophila (Chlamydia) pneumoniae in the Alzheimer's brain. FEMS Immunology and Medical Microbiology 48, 355366CrossRefGoogle ScholarPubMed
202Paradowski, B. et al. (2007) Evaluation of CSF-Chlamydia pneumoniae, CSF-tau, and CSF-Abeta42 in Alzheimer's disease and vascular dementia. Journal of Neurology 254, 154159CrossRefGoogle ScholarPubMed
203Appelt, D.M. et al. (2008) Inhibition of apoptosis in neuronal cells infected with Chlamydophila (Chlamydia) pneumoniae. BMC Neuroscience 9, 13CrossRefGoogle ScholarPubMed
204Ring, R.H. and Lyons, J.M. (2000) Failure to detect Chlamydia pneumoniae in the late-onset Alzheimer's brain. Journal of Clinical Microbiology 38, 25912594CrossRefGoogle ScholarPubMed
205Kornhuber, H.H. (1996) Propionibacterium acnes in the cortex of patients with Alzheimer's disease. European Archives of Psychiatry and Clinical Neuroscience 246, 108109CrossRefGoogle ScholarPubMed
206Kornhuber, H.H. (1996) Reply on critical comments on Propionibacterium acnes in the cortex of patients with Alzheimer's disease “ by Kornhuber, H.H. (Eur Arch Psychiatry Clin Neurosci, 246:108-109) by J. Bauer; Gottfries, G.G. and Försti, H. European Archives of Psychiatry and Clinical Neuroscience 246, 226Google Scholar
207Hudson, A.P. et al. (2000) Chlamydia pneumoniae, APOE genotype, and Alzheimer's disease. In Chlamydial Basis of Chronic Diseases (Dolmer, L., ed.), pp. 121–36, Robert Koch Institute, Springer Verlag, New YorkCrossRefGoogle Scholar
208Delahaye, F. et al. (2005) Propionibacterium acnes infective endocarditis. Study of 11 cases and review of literature. Archives desMaladies Coeur et des Vaisseaux 98, 12121218Google ScholarPubMed
209Brook, I. (2008) Microbiology and management of joint and bone infections due to anaerobic bacteria. Journal of Orthopaedic Science 13, 160169CrossRefGoogle ScholarPubMed
210Honjo, K., van Reekum, R. and Verhoeff, N.P. (2009) Alzheimer's disease and infection: do infectious agents contribute to progression of Alzheimer's disease? Alzheimer's Dementia 5, 348360CrossRefGoogle ScholarPubMed
211MacIntyre, A. et al. (2003) Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells. Journal of Neuroscience Research 71, 740750CrossRefGoogle ScholarPubMed
212Albert, N.M. (2000) Inflammation and infection in acute coronary syndrome. Journal of Cardiovascular Nursing 15, 1326CrossRefGoogle ScholarPubMed
213Arking, E.J. et al. (1999) Ulrastructural analysis of Chlamydia Pneumoniae in the Alzheimer's brain. Pathogenesis 1, 201211Google Scholar
214Dreses-Werringloer, U. et al. (2006) Chlamydophila (Chlamydia) pneumoniae infection of human astrocytes and microglia in culture displays an active, rather than a persistent, phenotype. American Journal of the Medical Sciences 332, 168174CrossRefGoogle ScholarPubMed
215Dreses-Werringloer, U. et al. (2009) Initial characterization of Chlamydophila (Chlamydia) pneumoniae cultured from the late-onset Alzheimer brain. International Journal of Medical Microbiology 299, 187201CrossRefGoogle ScholarPubMed
216Nochlin, D. et al. (1999) Failure to detect Chlamydia pneumoniae in brain tissues of Alzheimer's disease. Neurology 53, 1888CrossRefGoogle ScholarPubMed
217Gieffers, J. et al. (2000) Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer's disease patients. Journal of Clinical Microbiology 38, 881882CrossRefGoogle ScholarPubMed
218Preza, D. et al. (2008) Bacterial profiles of root caries in elderly patients. Journal of Clinical Microbiology 46, 20152021CrossRefGoogle ScholarPubMed
219Kornhuber, H.H. (1995) Chronic anaerobic cortical infection in Alzheimer's disease: Propionibacterium acnes. Neurology, Psychiatry and Brain Research 3, 177182Google Scholar
220Kornhuber, H.H. (1997) Cerebral microangiopathy, anaerobic infection and the prevention of Alzheimer's disease. Neurology, Psychiatry and Brain Research 5, 209212Google Scholar
221Howard, J. and Pilkington, G.J. (1992) Fibronectin staining detects micro-organisms in aged and Alzheimer's disease brain. Neuroreport 3, 615618CrossRefGoogle ScholarPubMed
222Fenesy, K.E. (1998) Periodontal disease: an overview for physicians. Mount Sinai Journal of Medicine 65, 362369Google ScholarPubMed
223Kohbata, S. and Beaman, B.L. (1991) L-dopa-responsive movement disorder caused by Nocardia asteroides localized in the brains of mice. Infection and Immunity 59, 181191CrossRefGoogle ScholarPubMed
224Malaguarnera, M. et al. (2004) Helicobacter pylori and Alzheimer's disease: a possible link. European Journal of Internal Medicine 15, 381386CrossRefGoogle ScholarPubMed
225Kountouras, J. et al. (2006) Relationship between Helicobacter pylori infection and Alzheimer disease. Neurology 66, 938940CrossRefGoogle ScholarPubMed
226Kountouras, J. et al. (2009) Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer's disease. International Journal of Neuroscience 119, 765777CrossRefGoogle ScholarPubMed
227Kountouras, J. et al. (2007) Association between Helicobacter pylori infection and mild cognitive impairment. European Journal of Neurology 14, 976982CrossRefGoogle ScholarPubMed
228Jamieson, G.A. et al. (1992) Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type. Journal of Pathology 167, 365368CrossRefGoogle ScholarPubMed
229Bertrand, P. et al. (1993) Distribution of herpes simplex virus type 1 DNA in selected areas of normal and Alzheimer's disease brains: a PCR study. Neurodegeneration 2, 201208Google Scholar
230Xu, F. et al. (2006) Trends in Herpes simplex virus type 1 and type 2 seroprevalence in the United States. Journal of the American Medical Association 296, 964973CrossRefGoogle ScholarPubMed
231Sequiera, L.W. et al. (1979) Detection of herpes-simplex viral genome in brain tissue. Lancet 2, 609612CrossRefGoogle ScholarPubMed
232Middleton, P.J. et al. (1980) Herpes-simplex viral genome and senile and presenile dementias of Alzheimer and Pick. Lancet 1, 1038Google ScholarPubMed
233Pogo, B.G. and Elizan, T.S. (1985) Search for viral DNA sequences in Alzheimer brain tissue. Lancet 1, 978979CrossRefGoogle ScholarPubMed
234Pogo, B.G., Casals, J. and Elizan, T.S. (1987) A study of viral genomes and antigens in brains of patients with Alzheimer's disease. Brain 110, 907915CrossRefGoogle ScholarPubMed
235Walker, D.G., O'Kusky, J.R. and McGeer, P.L. (1989) In situ hybridization analysis for herpes simplex virus nucleic acids in Alzheimer disease. Alzheimer Disease and Associated Disorder 3, 123131CrossRefGoogle ScholarPubMed
236Itzhaki, R.F. et al. (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet 349, 241244CrossRefGoogle ScholarPubMed
237Itabashi, S. et al. (1997) Herpes simplex virus and risk of Alzheimer's disease. Lancet 349, 1102CrossRefGoogle ScholarPubMed
238Lin, W.R. et al. (1998) Alzheimer's disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimer's Reports 1, 173178Google Scholar
239Beffert, U. et al. (1998) HSV-1 in brain and risk of Alzheimer's disease. Lancet 351, 13301331CrossRefGoogle ScholarPubMed
240Beffert, U. et al. (1998) Herpes simplex virus type 1 in brain, apolipoprotein E genotype and Alzheimer's disease. McGill Journal of Medicine 4, 48Google Scholar
241Wozniak, M.A., Mee, A.P. and Itzhaki, R.F. (2009) Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. Journal of Pathology 217, 131138CrossRefGoogle ScholarPubMed
242Wozniak, M.A. et al. (2005) Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer's disease patients. Journal of Medical Virology 75, 300306CrossRefGoogle ScholarPubMed
243Renvoize, E.B., Awad, I.O. and Hambling, M.H. (1987) A sero-epidemiological study of conventional infectious agents in Alzheimer's disease. Age and Ageing 16, 311314CrossRefGoogle ScholarPubMed
244Ounanian, A. et al. (1990) Antibodies to viral antigens, xenoantigens, and autoantigens in Alzheimer's disease. Journal of Clinical Laboratory Analysis 4, 367375CrossRefGoogle ScholarPubMed
245Letenneur, L. et al. (2008) Seropositivity to herpes simplex virus antibodies and risk of Alzheimer's disease: a population-based cohort study. PLoS One 3, 3637CrossRefGoogle ScholarPubMed
246Lin, W.R. et al. (2002) Herpesviruses in brain and Alzheimer's disease. Journal of Pathology 197, 395402CrossRefGoogle ScholarPubMed
247Renvoize, E.B. et al. (1979) Possible association of Alzheimer's disease with HLA- BW15 and cytomegalovirus infection. Lancet 1, 1238Google ScholarPubMed
248Aiello, A. et al. (2006) The influence of latent viral infection on rate of cognitive decline over 4 years. Journal of the American Geriatrics Society 54, 10461054CrossRefGoogle ScholarPubMed
249Matsuse, T. et al. (1994) Immunohistochemical and in situ hybridisation detection of adenovirus early region 1A (E1A) gene in the microglia of human brain tissue. Journal of Clinical Pathology 47, 275277CrossRefGoogle ScholarPubMed
250Igata, T. et al. (1997) Dementia and Borna disease virus. Dementia and Geriatric Cognitive Disorders 9, 2425CrossRefGoogle Scholar
251Yamaguchi, K. et al. (1999) Detection of borna disease virus-reactive antibodies from patients with psychiatric disorders and from horses by electrochemiluminescence immunoassay. Clinical and Diagnostic Laboratory Immunology 6, 696700CrossRefGoogle ScholarPubMed
252Chalmers, R.M., Thomas, D.R. and Salmon, R.L. (2005) Borna disease virus and the evidence for human pathogenicity: a systematic review. QJM 98, 255274CrossRefGoogle ScholarPubMed
253Stahl, T. et al. (2006) Viral-induced inflammation is accompanied by beta-amyloid plaque reduction in brains of amyloid precursor protein transgenic Tg2576 mice. European Journal of Neuroscience 24, 19231934CrossRefGoogle ScholarPubMed
254Rempel, H.C. and Pulliam, L. (2005) HIV-1 Tat inhibits neprilysin and elevates amyloid beta. AIDS (London, England) 19, 127135CrossRefGoogle ScholarPubMed
255Lang, W. et al. (1989) Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland. Acta Neuropathologica 77, 379390CrossRefGoogle ScholarPubMed
256Hook, E.W. III (1989) Syphilis and HIV infection. Journal of Infectious Diseases 160, 530534CrossRefGoogle ScholarPubMed
257Comandini, U.V. et al. (1997) Chlamydia pneumoniae respiratory infections among patients infected with the human immunodeficiency virus. European Journal of Clinical Microbiology and Infectious Diseases 16, 720726CrossRefGoogle ScholarPubMed
258Tobian, A.A. and Quinn, T.C. (2009) Herpes simplex virus type 2 and syphilis infections with HIV: an evolving synergy in transmission and prevention. Current Opinion in HIV and AIDS 4, 294299CrossRefGoogle ScholarPubMed
259Burgos, J.S. et al. (2006) Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. Journal of Virology 80, 53835387CrossRefGoogle ScholarPubMed
260Miller, R.M. and Federoff, H.J. (2008) Isoform-specific effects of ApoE on HSV immediate early gene expression and establishment of latency. Neurobiology of Aging 29, 7177CrossRefGoogle ScholarPubMed
261Miklossy, J. et al. (2006) Beta-amyloid deposition and Alzheimer's type changes induced by Borrelia spirochetes. Neurobiology of Aging 27, 228236CrossRefGoogle ScholarPubMed
262Little, C.S. et al. (2004) Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiology of Aging 25, 419429CrossRefGoogle ScholarPubMed
263Hammond, C. et al. (2006) Antibiotic alters inflammation in the mouse brain during persistent Chlamydia pnemoniae infection. In Alzheimer's Disease: New Advances (Igbal, K., Winblat, B. and Avila, J. eds), pp. 295299, Medimond, BolognaGoogle Scholar
264Cribbs, D.H. et al. (2000) Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer's Aβ peptide. Biochemistry 39, 59885994CrossRefGoogle Scholar
265Satpute-Krishnan, P., DeGiorgis, J.A. and Bearer, E.L. (2003) Fast anterograde transport of herpes simplex virus: role for the amyloid precursor protein of Alzheimer's disease. Aging Cell 2, 305318CrossRefGoogle ScholarPubMed
266Wozniak, M.A. et al. (2007) Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neuroscience Letters 429, 95100CrossRefGoogle ScholarPubMed
267Zambrano, A. et al. (2008) Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1. Journal of Alzheimer's Disease 14, 259269CrossRefGoogle ScholarPubMed
268Wozniak, M.A., Frost, A.L. and Itzhaki, R.F. (2009) Alzheimer's disease-specific tau phosphorylation is induced by herpes simplex virus type 1. Journal of Alzheimer's Disease 16, 341350CrossRefGoogle ScholarPubMed
269Leinonen, M. (1993) Pathogenetic mechanisms and epidemiology of Chlamydia pneumoniae. European Heart Journal 14 (Suppl), 5761Google ScholarPubMed
270Boggian, I. et al. (2000) Asymptomatic herpes simplex type 1 virus infection of the mouse brain. Journal of Neurovirology 6, 303313CrossRefGoogle ScholarPubMed
271Valyi-Nagy, T. et al. (2000) Herpes simplex virus type 1 latency in the murine nervous system is associated with oxidative damage to neurons. Virology 278, 309321CrossRefGoogle ScholarPubMed
272Fox, A. (1990) Role of bacterial debris in inflammatory diseases of the joint and eye. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica 98, 957968CrossRefGoogle ScholarPubMed
273Stimpson, S.A. et al. (1986) Arthropathic properties of cell wall polymers from normal flora bacteria. Infection and Immunity 51, 240249CrossRefGoogle ScholarPubMed
274Fleming, T.J., Wallsmith, D.E. and Rosenthal, R.S. (1986) Arthropathic properties of gonococcal peptidoglycan fragments: implications for the pathogenesis of disseminated gonococcal disease. Infection and Immunity 52, 600608CrossRefGoogle ScholarPubMed
275Palaniyar, N. et al. (2002) Pulmonary innate immune proteins and receptors that interact with gram-positive bacterial ligands. Immunobiology 205, 575594CrossRefGoogle ScholarPubMed
276Gebbink, M.F. et al. (2005) Amyloids–a functional coat for microorganisms. Nature Reviews. Microbiology 3, 333341CrossRefGoogle ScholarPubMed
277Hammer, N.D. et al. (2008) Amyloids: friend or foe? Journal of Alzheimer's Disease 13, 407419CrossRefGoogle ScholarPubMed
278Gophna, U. et al. (2001) Curli fibers mediate internalization of Escherichia coli by eukaryotic cells. Infection and Immunity 69, 26592665CrossRefGoogle ScholarPubMed
279Ben Nasr, A. et al. (1996) Assembly of human contact phase proteins and release of bradykinin at the surface of curli-expressing Escherichia coli. Molecular Microbiology 20, 927935CrossRefGoogle ScholarPubMed
280Olsén, A., Jonsson, A. and Normark, S. (1989) Fibronectin binding mediated by a novel class of surface organelles on Escherichia coli. Nature 338, 652655CrossRefGoogle ScholarPubMed
281Sjöbring, U., Pohl, G. and Olsén, A. (1994) Plasminogen, absorbed by Escherichia coli expressing curli or by Salmonella enteritidis expressing thin aggregative fimbriae, can be activated by simultaneously captured tissue-type plasminogen activator (t-PA). Molecular Microbiology 14, 443445CrossRefGoogle ScholarPubMed
282Hammar, M. et al. (1995) Expression of two csg operons is required for production of fibronectin- and congo red-binding curli polymers in Escherichia coli K-12. Molecular Microbiology 18, 661670CrossRefGoogle ScholarPubMed
283Umemoto, T., Li, M. and Namikawa, I. (1997) Adherence of human oral spirochetes by collagen-binding proteins. Microbiology and Immunology 41, 917923CrossRefGoogle ScholarPubMed
284Crack, P.J. and Bray, P.J. (2007) Toll-like receptors in the brain and their potential roles in neuropathology. Immunology and Cell Biology 85, 476480CrossRefGoogle ScholarPubMed
285Lorenz, E. et al. (2002) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Archives of Internal Medicine 162, 10281032CrossRefGoogle ScholarPubMed
286Kiechl, S., Wiedermann, C.J. and Willeit, J. (2003) Toll-like receptor 4 and atherogenesis. Annals of Medicine 35, 164171CrossRefGoogle ScholarPubMed
287Akira, S. and Takeda, K. (2004) Functions of toll-like receptors: lessons from KO mice. Comptes Rendus Biologies 327, 581589CrossRefGoogle ScholarPubMed
288Tobias, P. and Curtiss, L.K. (2005) Thematic review series: the immune system and atherogenesis. Paying the price for pathogen protection: toll receptors in atherogenesis. Journal of Lipid Research 46, 404411CrossRefGoogle ScholarPubMed
289Turvey, S.E. and Hawn, T.R. (2006) Towards subtlety: understanding the role of Toll-like receptor signaling in susceptibility to human infections. Clinical Immunology 120, 19CrossRefGoogle ScholarPubMed
290Bulut, Y. et al. (2001) Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. Journal of Immunology 167, 987994CrossRefGoogle ScholarPubMed
291Sellati, T.J. et al. (1998) Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytic cells via a CD14-dependent pathway distinct from that used by lipopolysaccharide. Journal of Immunology 160, 54555464CrossRefGoogle Scholar
292Schroeder, N.W. et al. (2004) Lipopolysaccharide binding protein binds to triacylated and diacylated lipopeptides and mediates innate immune responses. Journal of Immunology 173, 26832691CrossRefGoogle Scholar
293Radolf, J.D. et al. (1995) Characterization of outer membranes isolated from Borrelia burgdorferi, the Lyme disease spirochete. Infection and Immunity 63, 21542163CrossRefGoogle ScholarPubMed
294Ramesh, G. et al. (2003) Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes. European Journal of Immunology 33, 25392550CrossRefGoogle ScholarPubMed
295Ratner, A.J. et al. (2005) Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces. Proceedings of the National Academy of Sciences of the United States of America 102, 34293434Google Scholar
296van den Blink, B. et al. (2001) p38 mitogen-activated protein kinase inhibition increases cytokine release by macrophages in vitro and during infection in vivo. Journal of Immunology 166, 582587Google Scholar
297Van der Goot, F.G.E. (2001) Pore Forming Toxins. Springer Verlag, BerlinCrossRefGoogle Scholar
298Gekara, N.O. et al. (2007) The multiple mechanisms of Ca(2+) signalling by listeriolysin O, the cholesterol-dependent cytolysin of Listeria monocytogenes. Cellular Microbiology 9, 20082021CrossRefGoogle ScholarPubMed
299Gonzalez, M.R. (2008) Bacterial pore-forming toxins: The (w)hole story ? Cellular and Molecular Life Sciences 65, 493507CrossRefGoogle Scholar
300Gekara, N.O. and Weiss, S. (2004) Lipid rafts clustering and signalling by listeriolysin O. Biochemical Society Transactions 32, 712714CrossRefGoogle ScholarPubMed
301Cossart, P. and Lecuit, M. (1998) Interactions of Listeria monocytogenes with mammalian cells during entry and actin-based movement: bacterial factors, cellular ligands and signaling. EMBO Journal 17, 37973806CrossRefGoogle ScholarPubMed
302Kayal, S. et al. (1999) Listeriolysin O-dependent activation of endothelial cells during infection with Listeria monocytogenes: activation of NF-kappa B and upregulation of adhesion molecules and chemokines. Molecular Microbiology 31, 17091722CrossRefGoogle ScholarPubMed
303Hamon, M.A. et al. (2007) Histone modifications induced by a family of bacterial toxins. Proceedings of the National Academy of Sciences of the United States of America 104, 1346713472CrossRefGoogle ScholarPubMed
304Pipkin, M.E. and Lieberman, J. (2007) Delivering the kiss of death: Progress on understanding how perforin works. Current Opinion in Immunology 19, 301308CrossRefGoogle ScholarPubMed
305Blanco, D.R. et al. (1999) Immunization with Treponema pallidum outer membrane vesicles induces high-titer complement-dependent treponemicidal activity and aggregation of T. pallidum rare outer membrane proteins (TROMPs). Journal of Immunology 163, 27412746CrossRefGoogle ScholarPubMed
306Lawrenz, M.B. et al. (2003) Effect of complement component C3 deficiency on experimental Lyme borreliosis in mice. Infection and Immunity 71, 44324440CrossRefGoogle ScholarPubMed
307Kraiczy, P. et al. (2001) Mechanism of complement resistance of pathogenic Borrelia burgdorferi isolates. International Immunopharmacology 1, 393401CrossRefGoogle ScholarPubMed
308Stanley, L.C. et al. (1994) Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimer's disease. Journal of Neuropathology and Experimental Neurology 53, 231238CrossRefGoogle ScholarPubMed
309Brabers, N.A. and Nottet, H.S. (2006) Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia. European Journal of Clinical Investigation 36, 447458CrossRefGoogle ScholarPubMed
310Sheng, J.G. et al. (1996) In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurobiology of Aging 17, 761766CrossRefGoogle ScholarPubMed
311Goldgaber, D. et al. (1989) Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 86, 76067610CrossRefGoogle ScholarPubMed
312Barger, S.W. et al. (2008) Relationships between expression of apolipoprotein E and beta-amyloid precursor protein are altered in proximity to Alzheimer beta-amyloid plaques: potential explanations from cell culture studies. Journal of Neuropathology and Experimental Neurology 67, 773783CrossRefGoogle ScholarPubMed
313Li, Y. et al. (2003) Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. Journal of Neuroscience 23, 16051611CrossRefGoogle ScholarPubMed
314Sheng, J.G. et al. (2000) Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Experimental Neurology 163, 388391CrossRefGoogle ScholarPubMed
315Sheng, J.G. et al. (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochemistry International 39, 341348CrossRefGoogle Scholar
316Li, Y. et al. (2000) Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. Journal of Neuroscience 20, 149155CrossRefGoogle ScholarPubMed
317Zhu, S.G. et al. (1999) Increased interleukin-1beta converting enzyme expression and activity in Alzheimer disease. Journal of Neuropathology and Experimental Neurology 58, 582587CrossRefGoogle ScholarPubMed
318Li, Y. et al. (2004) Microglial activation by uptake of fDNA via a scavenger receptor. Journal of Neuroimmunology 147, 5055CrossRefGoogle Scholar
319Barger, S.W. and Harmon, A.D. (1997) Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388, 878881CrossRefGoogle ScholarPubMed
320Tahara, K. et al. (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129, 30063019CrossRefGoogle ScholarPubMed
321Scholtzova, H. et al. (2009) Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. Journal of Neuroscience 29, 18461854CrossRefGoogle ScholarPubMed
322Kraiczy, P. and Würzner, R. (2006) Complement escape of human pathogenic bacteria by acquisition of complement regulators. Molecular Immunology 43, 3144CrossRefGoogle ScholarPubMed
323Pausa, M. et al. (2003) Serum-resistant strains of Borrelia burgdorferi evade complement-mediated killing by expressing a CD59-like complement inhibitory molecule. Journal of Immunology 170, 32143222CrossRefGoogle ScholarPubMed
324Rasley, A., Anguita, J. and Marriott, I. (2002) Borrelia burgdorferi induces inflammatory mediator production by murine microglia. Journal of Neuroimmunology 130, 2231CrossRefGoogle ScholarPubMed
325Hauss-Wegrzyniak, B., Vraniak, P.D. and Wenk, G.L. (2000) LPS-induced neuroinflammatory effects do not recover with time. Neuroreport 11, 17591763CrossRefGoogle Scholar
326Lehman, T.J. et al. (1983) Polyarthritis in rats following the systemic injection of Lactobacillus casei cell walls in aqueous suspension. Arthritis and Rheumatism 26, 12591265CrossRefGoogle ScholarPubMed
327Johannsen, L. (1993) Biological properties of bacterial peptidoglycan. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica 101, 337344CrossRefGoogle ScholarPubMed
328Schwab, J.H. (1993) Phlogistic properties of peptidoglycan-polysaccharide polymers from cell walls of pathogenic and normal-flora bacteria which colonize humans. Infection and Immunity 61, 45354539CrossRefGoogle ScholarPubMed
329Heiss, L.N. et al. (1994) Epithelial autotoxicity of nitric oxide: role in the respiratory cytopathology of pertussis. Proceedings of the National Academy of Sciences 91, 267270CrossRefGoogle ScholarPubMed
330Weinberg, G. and Miklossy, J. (2008) Iron and infection. Journal of Alzheimer's Diseases 13, 451463CrossRefGoogle Scholar
331Griffiths, E. (1991) Iron and bacterial virulence - a brief overview. Biological Methods 4, 713CrossRefGoogle ScholarPubMed
332Weinberg, E.D. (1992) Iron depletion: a defense against intracellular infection and neoplasia. Life Sciences 50, 12891297CrossRefGoogle ScholarPubMed
333Griffiths, W.J. et al. (2000) Localization of iron transport and regulatory proteins in human cells. QJM 93, 575587CrossRefGoogle ScholarPubMed
334Goodman, L. (1953) Alzheimer's disease; a clinico-pathologic analysis of twenty- three cases with a theory on pathogenesis. Journal of Nervous and Mental Disease 118, 97130CrossRefGoogle ScholarPubMed
335Bishop, G.M. et al. (2002) Iron: a pathological mediator of Alzheimer disease? Developmental Neuroscience 24, 184187CrossRefGoogle Scholar
336Miller, L.M. et al. (2006) Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with beta-amyloid deposits in Alzheimer's disease. Journal of Structural Biology 155, 3037CrossRefGoogle Scholar
337Lirk, P., Hoffmann, G. and Rieder, J. (2002) Inducible nitric oxide synthase – time for reappraisal. Curr Drug Targets – Inflammation and Allergy 1, 89108CrossRefGoogle ScholarPubMed
338Chan, E.D., Chan, J. and Schluger, N.W. (2001) What is the role of nitric oxide in murine and human host defense against tuberculosis? Current knowledge. American Journal of Respiratory Cell and Molecular Biology 25, 606612CrossRefGoogle ScholarPubMed
339Chakravortty, D. and Hensel, M. (2003) Inducible nitric oxide synthase and control of intracellular bacterial pathogens. Microbes and Infection 5, 621627CrossRefGoogle ScholarPubMed
340Shiloh, M.U. and Nathan, C.F. (2000) Reactive nitrogen intermediates and the pathogenesis of Salmonella and mycobacteria. Current Opinion in Microbiology 3, 3542CrossRefGoogle ScholarPubMed
341Bogdan, C. (2001) Nitric oxide and the immune response. Nature Immunology 2, 907916CrossRefGoogle ScholarPubMed
342Ohnishi, S., Koide, A. and Koide, S. (2001) The roles of turn formation and cross- strand interactions in fibrillization of peptides derived from the OspA single-layer beta-sheet. Protein Science 10, 20832092CrossRefGoogle ScholarPubMed
343Otzen, D. and Nielsen, P.H. (2008) We find them here, we find them there: functional bacterial amyloid. Cellular and Molecular Life Sciences 65, 910927CrossRefGoogle ScholarPubMed
344Chapman, M.R. et al. (2002) Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295, 851855CrossRefGoogle ScholarPubMed
345Larsen, P. et al. (2007) Amyloid adhesins are abundant in natural biofilms. Environmental Microbiology 9, 30773090CrossRefGoogle ScholarPubMed
346Jordal, P.B. et al. (2009) Widespread abundance of functional bacterial amyloid in Mycolata and other Gram-positive bacteria. Applied and Environmental Microbiology 75, 41014110CrossRefGoogle ScholarPubMed
347Wang, X., Hammer, N.D. and Chapman, M.R. (2008) The molecular basis of functional bacterial amyloid polymerization and nucleation. Journal of Biological Chemistry 283, 2153021539CrossRefGoogle ScholarPubMed
348Picken, M.M. (2000) The changing concepts of amyloid. Archives of Pathology and Laboratory Medicine 125, 3843CrossRefGoogle Scholar
349Hauss-Wegrzyniak, B. and Wenk, G.L. (2002) Beta-amyloid deposition in the brains of rats chronically infused with thiorphan or lipopolysaccharide: the role of ascorbic acid in the vehicle. Neuroscience Letters 322, 7578CrossRefGoogle ScholarPubMed
350Miklossy, J. et al. (2010) Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging. 31:15031515CrossRefGoogle ScholarPubMed
351Kitazawa, M. et al. (2005) Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. Journal of Neuroscience 25, 88438853CrossRefGoogle Scholar
352Knight, J.C. and Kwiatkowski, D. (1999) Inherited variability of tumor necrosis factor production and susceptibility to infectious disease. Proceedings of the Association of American Physicians 111, 290298CrossRefGoogle ScholarPubMed
353Shaw, M.A. et al. (2001) Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes. Genes and Immunity 2, 196204CrossRefGoogle ScholarPubMed
354Roy, S. et al. (1997) Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. Journal of Infectious Diseases 176, 530532CrossRefGoogle ScholarPubMed
355Marangoni, A. et al. (2004) Production of tumor necrosis factor alpha by Treponema pallidum, Borrelia burgdorferi s.l., and Leptospira interrogans in isolated rat Kupffer cells. FEMS Immunology and Medical Microbiology 40, 187191CrossRefGoogle ScholarPubMed
356Steere, A.C., Dwyer, E. and Winchester, R. (1990) Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. New England Journal of Medicine 323, 21923CrossRefGoogle ScholarPubMed
357Lagrange, P.H. and Abel, L. (1996) The genetic susceptibility to leprosy in humans. Acta Leprologica 10, 1127Google Scholar
358Collins, J.S. et al. (2000) Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative. American Journal of Medical Genetics 96, 8238303.0.CO;2-I>CrossRefGoogle ScholarPubMed
359McCusker, S.M. et al. (2001) Association between polymorphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer's disease and vascular dementia: a case-control study. Lancet 357, 436439CrossRefGoogle ScholarPubMed
360Gnjec, A. et al. (2008) Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease. Journal of Neuroinflammation 5, 36CrossRefGoogle ScholarPubMed
361Alves, C. et al. (2007) The role of the human histocompatibility antigens in the pathogenesis of neurological disorders. Revista de Neurologia 44, 298302CrossRefGoogle ScholarPubMed
362Ballerini, C. et al. (1999) HLA A2 allele is associated with age at onset of Alzheimer's disease. Annals of Neurology 45, 3974003.0.CO;2-4>CrossRefGoogle ScholarPubMed
363Griffin, W.S. et al. (1995) Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. Journal of Neuropathology and Experimental Neurology 54, 276281CrossRefGoogle ScholarPubMed
364Nicoll, J.A. et al. (2000) Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Annals of Neurology 47, 3653683.0.CO;2-G>CrossRefGoogle ScholarPubMed
365Minoretti, P. et al. (2006) Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease. Neuroscience Letters 391, 147149CrossRefGoogle ScholarPubMed
366Balistreri, C.R. et al. (2008) Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer's disease. Current Pharmaceutical Design 14, 26722677CrossRefGoogle ScholarPubMed
367Urosevic, N. and Martins, R.N. (2008) Infection and Alzheimer's disease: the APOE epsilon4 connection and lipid metabolism. Journal of Alzheimer's Disease 13, 421435CrossRefGoogle ScholarPubMed
368Licastro, F. et al. (2007) Genetic risk profiles for Alzheimer's disease: integration of APOE genotype and variants that up-regulate inflammation. Neurobiology of Aging 28, 16371643CrossRefGoogle ScholarPubMed
369Corder, E.H. et al. (1998) HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nature Medicine 4, 11821184CrossRefGoogle Scholar
370Itzhaki, R.F. et al. (2004) Infiltration of the brain by pathogens causes Alzheimer's disease. Neurobiology of Aging 25, 619627CrossRefGoogle ScholarPubMed
371Itzhaki, R.F. and Wozniak, M.A. (2006) Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer's disease and other disorders. Progress in Lipid Research 45, 7390CrossRefGoogle ScholarPubMed
372Bhattacharjee, P.S. et al. (2008) Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1. Experimental Eye Research 87, 122130CrossRefGoogle ScholarPubMed
373Itzhaki, R.F. and Wozniak, M.A. (2010) Alzheimer's disease and infection: do infectious agents contribute to progression of Alzheimer's disease? Alzheimer's Dementia 6, 8384CrossRefGoogle ScholarPubMed
374Perry, V.H., Cunningham, C. and Holmes, C. (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nature Reviews. Immunology 7, 161167CrossRefGoogle ScholarPubMed
375Perry, V.H., Nicoll, J.A. and Holmes, C. (2010) Microglia in neurodegenerative disease. Nature Reviews. Neurology 6, 193201CrossRefGoogle ScholarPubMed
376Holmes, C. and Cotterell, D. (2009) Role of infection in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs 23, 9931002CrossRefGoogle ScholarPubMed
377Kamer, A.R. et al. (2009) TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer's disease patients and normal subjects. Journal of Neuroimmunology 216, 9297CrossRefGoogle ScholarPubMed
378Blatz, R. et al. (2005) Neurosyphilis and neuroborreliosis. Retrospective evaluation of 22 cases. Der Nervenarzt 76, 724732CrossRefGoogle Scholar
379Bolintineanu, D. et al. (2009) Antimicrobial mechanism of pore-forming protegrin peptides: 100 pores to kill E. coli. Peptides 31, 18CrossRefGoogle ScholarPubMed
380Kobayashi, N. et al. (2008) Binding sites on tau proteins as components for antimicrobial peptides. Biocontrol Science 13, 4956CrossRefGoogle ScholarPubMed
381Shaftel, S.S. et al. (2007) Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. Journal of Clinical Investigation 117, 15951604CrossRefGoogle ScholarPubMed
Figure 0

Figure 1. Distribution of spirochetes in the atrophic form of general paresis and in the frontal cortex of an Alzheimer disease (AD) patient with Lyme neuroborreliosis. Spirochetes form plaque-like masses (a,c) and disseminate as individual filaments (b,d) in general paresis (a,b) and AD (c,d), which are identical to senile plaques and curly fibres. (a,c) Bosma Steiner silver technique for the visualisation of spirochetes. (b) T. pallidum-specific polyclonal antibody. (d) Gallyas silver technique. Scale bars: 50 µm (a), 40 µm (c), 10 µm (b,d). All images were obtained from previously published studies: a (Ref. 124); b (Ref. 175); c, d (Ref. 149).

Figure 1

Figure 2. Spirochetes detected in the frontal cortex of neuropathologically confirmed Alzheimer disease cases. Spirochetes in an immature senile plaque detected by a cocktail of antibodies against Borrelia burgdorferi (a), in a mature plaque detected by in situ hybridisation (b, arrows) using Borrelia-specific probes, and in an amorphous plaque detected by antibacterial peptidoglycan antibody (c). (d) The central part of panel c at higher magnification. Arrows indicate helical spirochetes with the same morphology as observed in b. Scale bars: 80 µm (a), 30 µm (b), 80 µm (c), 20 µm (d). Images are from previously published studies: a,b (Ref. 149); c,d (Ref. 188).

Figure 2

Table 1. Detection of spirochetes in AD

Figure 3

Table 2. Detection of Chlamydophyla pneumoniae and other bacteria in AD

Figure 4

Table 3. Detection of HSV-1 in AD

Figure 5

Figure 3. Sources and dissemination of pathogens associated with Alzheimer disease.

Figure 6

Figure 4. Schematic representation of signalling pathways implicated in host–pathogen interactions in Alzheimer disease. Pattern recognition receptors (PRRs) recognise conserved structural components of microorganisms, called pathogen-associated molecular patterns (PAMPs) or ligands, which include peptidoglycan (PGN), lipoteichoic acid (LTA), flagellin (FLA), bacterial lipoprotein (BLP) and nucleic acid structures, such as bacterial CpG DNA or viral RNA, unique to bacteria and viruses. Lipopolysaccharide (LPS) is recognised following its binding to lipoprotein binding protein (LBP). Only Toll-like receptors (TLRs) have a cytoplasmic domain for signal transduction. Plasma-membrane-localised TLRs include TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10, whereas endosomal TLRs include TLR3, TLR7, TLR8 and TLR9. TLR9 is responsible for the recognition of CpG islands of bacterial DNA. Complex interactions between pathogen-associated molecular patterns (PAMPs), pattern recognition receptors (PRRs) and TLR signalling pathways have a major role in linking innate and adaptive immunity and maintaining pathogen-free host tissues. Mammals use antimicrobial peptides (AMPs) as part of their innate immune defences to destroy invading pathogens. In contrast, in a similar way, pore-forming bacterial surface proteins are also able to destroy host cells. Evasion of pathogens from destruction by the host immune defences will result in chronic persistent infection and host cell destruction. APP, amyloid precursor protein; Aβ, amyloid beta; CD14, cluster of differentiation 14; NF-κB, nuclear factor-kappa B; MALP2, mycoplasma diacylated lipopeptide 2; p38 MAPK, mitogen-activated protein kinase; JNK, c-Jun kinase; MAC, membrane attack complex; MD2, lymphocyte antigen 96; Akt, serine/threonine protein kinase Akt1; IRF, interferon regulatory factor; IL, interleukin; TNF, tumour necrosis factor; COX2, cyclooxygenase 2; IFN, interferon, CREB, cAMP response element binding.