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Emerging roles of pathogens in Alzheimer disease

  • Judith Miklossy (a1)

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.

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Corresponding author

*Corresponding author: Judith Miklossy, 1921 Martigny-Croix CP 16, 1921, Switzerland. E-mail: judithmiklossy@bluewin.ch

References

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1Alzheimer, A. (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medicin 64, 146148
2Alzheimer, A. (1911) Über eigenartige Krankheitsfälle des späteren Alters. Zeitschrift für die gesamte Neurologie und Psychiatrie 4, 356385
3Katzman, R. (1976) The prevalence and malignancy of Alzheimer's disease: a major killer. Archives of Neurology 33, 217218
4Terry, R.D. and Davies, P. (1980) Dementia of the Alzheimer type. Annual Review of Neuroscience 3, 7795
5Blocq, P. and Marinesco, G. (1892) Sur les lésions et la pathogénie de l'épilepsie dite essentielle. Semaine Médicale 12, 445446
6Redlich, E. (1898) Über miliare Sklerose der Hirnrinde bei seniler Atrophie. Jahrbuch für Psychiatrie und Neurologie 17, 208216
7Gallyas, F. (1971) Silver staining of Alzheimer's neurofibrillary changes by means of physical development. Acta Morpholpgica-Academiae Scientiarum Hungaricae 19, 18
8Simchowicz, T. (1911) Histologische Studien über die senile Demenz. Histologie Und Histopathologie Arb über Grosshirnrinde 4, 367444
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, 572580
10Kang, J. et al. (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733736
11Selkoe, D.J. (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends in Cell Biology 8, 447453
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, 885890
13Schubert, D. et al. (1988) Amyloid beta protein precursor is possibly a heparan sulfate proteoglycan core protein. Science 241, 17591763
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, 175182
15Li, Q.X. et al. (1999) The amyloid precursor protein of Alzheimer disease in human brain and blood 66, 567574
16Allen, J.S. et al. (1991) Alzheimer's disease: beta-amyloid precursor protein mRNA expression in mononuclear blood cells. Neuroscience Letters 132, 109112
17Mönning, U. et al. (1990) Synthesis and secretion of Alzheimer amyloid beta A4 precursor protein by stimulated human peripheral blood leucocytes. FEBS Letters 277, 261266
18Ledoux, S. et al. (1993) Amyloid precursor protein in peripheral mononuclear cells is up-regulated with cell activation. Journal of Immunology 150, 55665575
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, 1234512352
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, 3506935076
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, 64486453
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, 88768884
23Walsh, D.M. et al. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535539
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, 567577
25Cerf, E. et al. (2009) Antiparallel beta-sheet: a signature structure of the oligomeric amyloid beta- peptide. Biochemical Journal 421, 415423
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, 189197
27Lashuel, H.A. et al. (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291
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, 391402
29Ayala, P. et al. (2005) The pilus and porin of Neisseria gonorrhoeae cooperatively induce Ca(2+) transients in infected epithelial cells. Cellular Microbiology 7, 17361748
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, 339352
31Soscia, S.J. et al. (2010) The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 5, e9505
32Kidd, M. (1963) Paired helical filaments in electron microscopy of Akzheimer's disease. Nature 197, 192193
33Terry, R.D. (1963) The fine structure of neurofibrillary tangles in Alzheimer's disease. Journal of Neuropathology and Experimental Neurology 22, 629642
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.
35Lee, V.M.-Y. (1995) Disruption of the cytoskeleton in Alzheimer's disease. Current Opinion in Neurobiology 5, 663668
36Lu, P.J. et al. (1999) The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784788
37Sherrington, R. et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754760
38Selkoe, D.J. (1996) Amyloid beta-protein and the genetics of Alzheimer's disease. Journal of Biological Chemistry 271, 1829518298
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, 20952097
40Tanzi, R.E. and Bertram, L. (2001) New frontiers in Alzheimer's disease genetics. Neuron 32, 181184
41Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353356
42Bertram, L. and Tanzi, R.E. (2005) The genetic epidemiology of neurodegenerative disease. Journal of Clinical Investigation 115, 14491457
43Nagy, Z. (2005) The last neuronal division: a unifying hypothesis for the pathogenesis of Alzheimer's disease. Journal of Cellular and Molecular Medicine 9, 531541
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, 85528559
45Goate, A. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704706
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, 345347
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, 219222
48Wasco, W. et al. (1995) Familial Alzheimer's chromosome 14 mutations. Nature Medicine 1, 848
49Perez-Tur, J. et al. (1995) A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 7, 297301
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, 655662
51Levy-Lahad, E. et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973977
52Citron, M. et al. (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360, 672674
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, 514516
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, 13361340
55Duff, K. et al. (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710713
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, 864870
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, 10051013
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, 20252030
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, 6772
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), 165167
61McGeer, P.L. and McGeer, E.G. (2001) Polymorphisms in inflammatory genes and the risk of Alzheimer disease. Archives of Neurology 58, 17901792
62Bertram, L. et al. (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature Genetics 39, 1723
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, 19531958
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, 15861593
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, 279280
66Perry, E.K. et al. (1981) Neurochemical activities in human temporal lobe related to aging and Alzheimer-type changes. Neurobiology of Aging 2, 251256
67Rossor, M.N. (1982) Neurotransmitters and CNS disease. Dementia. Lancet 2, 12001204
68Fowler, C.J. et al. (1992) Neurotransmitter, receptor and signal transduction disturbances in Alzheimer's disease. Acta Neurologica Scandinavica 139 (Suppl), 5962
69Davies, P. and Maloney, A.J. (1976) Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2, 1403
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, 332358
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, 10421045
72Pappolla, M.A. et al. (1996) The heat shock/oxidative stress connection. Relevance to Alzheimer disease. Molecular and Chemical Neuropathology 28, 2134
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, 447454
74Nunomura, A. et al. (2006) Involvement of oxidative stress in Alzheimer disease. Journal of Neuropathology and Experimental Neurology 65, 631641
75Parker, W.D. Jr. (1991) Cytochrome oxidase deficiency in Alzheimer's disease. Annals of the New York Academy of Sciences 640, 5964
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, 200210
77Crapper, D.R., Krishnan, S.S. and Dalton, A.J. (1973) Brain aluminum distribution in Alzheimer's disease and experimental neurofibrillary degeneration. Science 180, 511513
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, 327340
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, 169183
80Khachaturian, Z.S. (1994) Calcium hypothesis of Alzheimer's disease and brain aging. Annals of the New York Academy of Sciences 747, 111
81Mori, H., Kondo, J. and Ihara, Y. (1987) Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235, 16411644
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, 99029906
83de la Torre, J.C. and Mussivand, T. (1993) Can disturbed brain microcirculation cause Alzheimer's disease? Neurological Research 15, 146153
84Esiri, M.M. et al. (1999) Cerebrovascular disease and threshold for dementia in the early stage of Alzheimer's disease. Lancet 354, 919920
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, 16
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, 813817
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, 5674
88Diaz, J.F. et al. (1991) Improved recognition of leukoaraiosis and cognitive impairment in Alzheimer's disease. Archives of Neurology 48, 10221025
89Kalaria, R.N. (2000) The role of cerebral ischemia in Alzheimer's disease. Neurobiology of Aging 21, 321330
90Suter, O.C. et al. (2002) Cerebral hypoperfusion generates cortical watershed microinfarcts in Alzheimer disease. Stroke 33, 19861992
91Miklossy, J. (2003) Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's disease. Neurological Research 25, 605610
92Muckle, T.J. and Roy, J.R. (1985) High-density lipoprotein cholesterol in differential diagnosis of senile dementia. Lancet 1, 11911193
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, 128146
94Averback, P. (1983) Two new lesions in Alzheimer's disease. Lancet 2, 1203
95Mann, D.M., Tucker, C.M. and Yates, P.O. (1988) Alzheimer's disease: an olfactory connection? Mechanisms of Aging and Development 42, 115
96Hardy, J.A. et al. (1986) An integrative hypothesis concerning the pathogenesis and progression of Alzheimer's disease. Neurobiology of Aging 7, 489502
97Christen-Zaech, S. et al. (2003) Early olfactory involvement in Alzheimer's disease. Canadian Journal of Neurological Sciences 30, 2025
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, 195200
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, 76117615
100McGeer, P.L. and Rogers, J. (1992) Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology 42, 447449
101Schwab, C. and McGeer, P.L. (2008) Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. Journal of Alzheimer's Disease 13, 359369
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, 195218
103McGeer, P.L. and McGeer, E.G. (2002) Local neuroinflammation and the progression of Alzheimer's disease. Journal of Neurovirology 8, 529538
104Webster, S. et al. (1997) Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer's disease. Neurobiology of Aging 18, 415421
105Stewart, W.F. et al. (1997) Risk of Alzheimer's disease and duration of NSAID use. Neurology 48, 626632
106Zandi, P.P. et al. (2000) Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology 59, 880886
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), S204
108Akiyama, H. et al. (2000) Inflammation and Alzheimer's disease. Neurobiology of Aging 21, 383421
109Fischer, O. (1907) Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz. Monatsschrift für Psychiatrie und Neurologie 22, 361372
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.
111Khachaturian, Z.S. (1985) Diagnosis of Alzheimer's disease. Archives of Neurology 42, 10971105
112Hübner, A.H. (1908) Zur Histopathologie der senilen Hirnrinde. Archives of Psychiatry and Neurology 46, 598609
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.).
114Pacheco e Silva, A.C. (1926-27) Espirochetose dos centros nervos. Memorias do hospicio de Juquery, anno III-IV, 127
115Pacheco e Silva, A.C. (1926) Localisation du Treponema Pallidum dans le cerveau des paralytiques généraux. Revista de Neurologia 2, 558565
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.
117Rizzo, C. (1931) Ricerche sulle spirochete nel cervello dei paralitici. Riv Pathol Nerv 37, 797814
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, London
119Noguchi, H. and Moore, J.W. (1913) A demonstration of Treponema pallidum in the brain of general paralysis cases. Journal of Experimental Medicine 17, 232238
120Merritt, H.H., Adams, R.D. and Solomon, H.C. (1946) Neurosyphilis, Oxford University Press, London
121Bonfiglio, F. (1908) Di speciali reperti in un caso di probabile sifilide cerebrale. Deutsche Pathologische Gesellschaft 34, 196206
122Vinken, P.J. and Bruyn, G.W. (1978) Handbook of Neurology, Vol. 33, Chapter 17, Elsevier, Amsterdam, New York
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, 515520
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.
125Marshall, B.J. and Warren, J.R. (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1, 13111315
126Laitinen, K. et al. (1997) Chlamydia pneumonia infection induces inflammatory changes in the aortas of rabbits. Infection and Immunity 65, 48324835
127Saikku, P. (1999) Epidemiology of Chlamydia pneumoniae in atherosclerosis. American Heart Journal 138 (Suppl), 500503
128Mendall, M.A. et al. (1994) Relation of Helicobacter pylori infection and coronary heart disease. British Heart Journal 71, 437439
129Martin de Argila, C. et al. (1995) High seroprevalence of Helicobacter pylori infection in coronary heart disease. Lancet 346, 310
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, 11101119
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, 322327
132Chiu, B. (1999) Multiple infections in carotid atherosclerotic plaques. American Heart Journal 138, S534S536
133Haraszthy, V.I. et al. (2000) Identification of periodontal pathogens in atheromatous plaques. Journal of Periodontology 71, 15541560
134Rassu, M. et al. (2001) Demonstration of Chlamydia pneumoniae in atherosclerotic arteries from various vascular regions. Atherosclerosis 158, 7379
135Martin, R.J. (2006) Infections and asthma. Clinics in Chest Medicine 27, 8798
136MacDowell, A.L. and Bacharier, L.B. (2005) Infectious triggers of asthma. Immunology and Allergy Clinics of North America 25, 4566
137Micillo, E. et al. (2000) Respiratory infections and asthma. Allergy 61 (Suppl), 4245
138Marttila, R.J. et al. (1977) Viral antibodies in the sera from patients with Parkinson disease. European Neurology 15, 2533
139Rott, R. et al. (1985) Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders. Science 228, 755756
140Beaman, B.L. (1994). Bacteria and neurodegeneration. In Neurodegenerative Diseases (Caino, D., ed.), pp. 319338, W.B. Saunders, Orlando, FL
141Gosztonyi, G. and Ludwig, H. (1995) Borna disease-neuropathology and pathogenesis. Current Topics in Microbiology and Immunology 190, 3973
142Salvatore, M. et al. (1997) Borna disease virus in brains of North American and European people with schizophrenia and bipolar disorder. Lancet 349, 18131814
143Langford, D. and Masliah, E. (2003) The emerging role of infectious pathogens in neurodegenerative diseases. Experimental Neurology 184, 553555
144Balin, B.J. et al. (1998) Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Medical Microbiology and Immunology 187, 2342
145Balin, B.J. et al. (2008) Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease. Journal of Alzheimer's Disease 13, 371380
146Miklossy, J. (1993) Alzheimer's disease – a spirochetosis? Neuroreport 4, 841848
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, 113118
148Miklossy, J. (2008) Chronic inflammation and amyloidogenesis in Alzheimer's disease – role of spirochetes. Journal of Alzheimer's Disease 13, 381391
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, 111
150Jamieson, G.A. et al. (1991) Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains. Journal of Medical Virology 33, 224227
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, 393405
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, 869874
153Luchsinger, J.A. et al. (2005) Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65, 545551
154Voisin, T. et al. (2003) Vascular risk factors and Alzheimer's disease. La Revue de Medecine Interne 24 (Suppl), 288291
155Ott, A. et al. (1996) Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia 39, 13921397
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, 437449
157Pihlstrom, B.L., Michalowicz, B.S. and Johnson, N.W. (2005) Periodontal diseases. Lancet 366, 18091820
158Gibson, F.C. III et al. (2004) Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 109, 28012806
159Mattila, K.J., Pussinen, P.J. and Paju, S. (2005) Dental infections and cardiovascular diseases: a review. Journal of Periodontology 76 (Suppl), 20852088
160Seppaa, B. and Ainamo, J. (1996) Dark field microscopy of the subgingival microflora in insulin-dependent diabetics. Journal of Clinical Periodontology 23, 6367
161Ling, L.J. et al. (2004) Association between human herpesviruses and the severity of periodontitis. Journal of Periodontology 75, 14791485
162Heydenrijk, K. et al. (2002) Microbiota around root-form endosseous implants: a review of the literature. International Journal of Oral and Maxillofacial Implants 17, 829838
163O'Brien-Simpson, N.M. et al. (2004) Antigens of bacteria associated with periodontitis. Periodontology 2000 35, 101134
164DeGraba, T.J. (2004) Immunogenetic susceptibility of atherosclerotic stroke: implications on current and future treatment of vascular inflammation. Stroke 35 (Suppl 1), 27122719
165Kolb, H. and Mandrup-Poulsen, T. (2005) An immune origin of type 2 diabetes? Diabetologia 48, 10381050
166Dewhirst, F.E. et al. (2000) The diversity of periodontal spirochetes by 16S rRNA analysis. Oral Microbiology and Immunology 15, 196202
167Gastinel, P. (1949) Précis de bactériologie médicale. In Collections de précis médicaux. Masson and Cie, Paris
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, 482485
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, 347350
170Burgdorfer, W. et al. (1982) Lyme disease-a tick-borne spirochetosis? Science 216, 13171319
171Chan, E.C. et al. (1996) Characterization of a 4.2-kb plasmid isolated from periodontopathic spirochetes. Oral Microbiology and Immunology 11, 365368
172Riviere, G.R. et al. (1991) Pathogen-related oral spirochetes from dental plaque are invasive. Infection and Immunity 59, 33773380
173Peters, S. et al. (1999) Adherence to and penetration through cells by oral treponemes. Oral Microbiology and Immunology 14, 379383
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, 11171122
175Miklossy, J. et al. (2008) Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. Journal of Neuroinflammation 5, 40
176Miklossy, J. et al. (1995) Senile plaques, neurofibrillary tangles and neuropil threads contain DNA? Journal of Spirochetal and Tick-borne Diseases 2, 15
177Jacquet, L. and Sézary, A. (1907) Des formes atypiques et dégénératives du tréponéme pâle. Bull mem Soc Med Hop Par 24, 114
178MacDonald, A.B. and Miranda, J.M. (1987) Concurrent neocortical borreliosis and Alzheimer's disease. Human Pathology 18, 759761
179Meer-Scherrer, L. et al. (2006) Lyme disease associated with Alzheimer's disease. Current Microbiology 52, 330332
180Gutacker, M. et al. (1998) Arguments against the involvement of Borrelia burgdorferi sensu lato in Alzheimer's disease. Research in Microbiology 149, 3135
181Marques, A.R. et al. (2000) Lack of evidence of Borrelia involvement in Alzheimer's disease. Journal of Infectious Diseases 182, 10061007
182Galbussera, A. et al. (2008) Lack of evidence for Borrelia burgdorferi seropositivity in Alzheimer disease. Alzheimer Disease and Associated Disorder 22, 308
183MacDonald, A.B. (2006) Transfection “Junk” DNA – a link to the pathogenesis of Alzheimer's disease? Medical Hypotheses 66, 11401141
184MacDonald, A.B. (2006) Plaques of Alzheimer's disease originate from cysts of Borrelia burgdorferi, the Lyme disease spirochete. Medical Hypotheses. 67, 592600
185Pappolla, M.A. et al. (1989) Concurrent neuroborreliosis and Alzheimer's disease: analysis of the evidence. Human Pathology 20, 753757
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, Boston
187Miklossy, J. et al. (1994) Further morphological evidence for a spirochetal etiology of Alzheimer's Disease. NeuroReport 5, 12011204
188Miklossy, J. et al. (1996) Bacterial peptidoglycan in neuritic plaques in Alzheimer's disease. Azheimer's Research 2, 95100
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, 4551
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, 65076512
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, 1790917914
192McLaughlin, R. et al. (1999) Alzheimer's disease may not be a spirochetosis. Neuroreport 10, 14891491
193Mattman, L.H. (1993) Cell Wall Deficient Forms: Stealth Pathogens (2nd edn), CRC Press, Inc, Boca Raton, FL.
194MacDonald, A.B. (1986) Borrelia in the brains of patients dying with dementia. Journal of the American Medical Association 256, 21952196
195Dupuis, M.J. (1988) Multiple neurologic manifestations of Borrelia burgdorferi infection. Revista de Neurologia 144, 765775
196Schaeffer, S. et al. (1994) Dementia in Lyme disease. Presse Medicale 23, 861
197Fallon, B.A. and Nields, J.A. (1994) Lyme disease: a neuropsychiatric illness. American Journal of Psychiatry 151, 1571–183
198Pennekamp, A. and Jaques, M. (1997) Chronic neuroborreliosis with gait ataxia and cognitive disorders. Praxis 86, 867869
199MacDonald, A.B. (1988) Concurrent neocortical borreliosis and Alzheimer's Disease. Annals of the New York Academy of Sciences 539, 468470
200Gérard, H.C. et al. (2005) The load of Chlamydia pneumoniae in the Alzheimer's brain varies with APOE genotype. Microbial Pathogenesis 39, 1926
201Gérard, H.C. et al. (2006) Chlamydophila (Chlamydia) pneumoniae in the Alzheimer's brain. FEMS Immunology and Medical Microbiology 48, 355366
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, 154159
203Appelt, D.M. et al. (2008) Inhibition of apoptosis in neuronal cells infected with Chlamydophila (Chlamydia) pneumoniae. BMC Neuroscience 9, 13
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, 25912594
205Kornhuber, H.H. (1996) Propionibacterium acnes in the cortex of patients with Alzheimer's disease. European Archives of Psychiatry and Clinical Neuroscience 246, 108109
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, 226
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 York
208Delahaye, F. et al. (2005) Propionibacterium acnes infective endocarditis. Study of 11 cases and review of literature. Archives desMaladies Coeur et des Vaisseaux 98, 12121218
209Brook, I. (2008) Microbiology and management of joint and bone infections due to anaerobic bacteria. Journal of Orthopaedic Science 13, 160169
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, 348360
211MacIntyre, A. et al. (2003) Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells. Journal of Neuroscience Research 71, 740750
212Albert, N.M. (2000) Inflammation and infection in acute coronary syndrome. Journal of Cardiovascular Nursing 15, 1326
213Arking, E.J. et al. (1999) Ulrastructural analysis of Chlamydia Pneumoniae in the Alzheimer's brain. Pathogenesis 1, 201211
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, 168174
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, 187201
216Nochlin, D. et al. (1999) Failure to detect Chlamydia pneumoniae in brain tissues of Alzheimer's disease. Neurology 53, 1888
217Gieffers, J. et al. (2000) Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer's disease patients. Journal of Clinical Microbiology 38, 881882
218Preza, D. et al. (2008) Bacterial profiles of root caries in elderly patients. Journal of Clinical Microbiology 46, 20152021
219Kornhuber, H.H. (1995) Chronic anaerobic cortical infection in Alzheimer's disease: Propionibacterium acnes. Neurology, Psychiatry and Brain Research 3, 177182
220Kornhuber, H.H. (1997) Cerebral microangiopathy, anaerobic infection and the prevention of Alzheimer's disease. Neurology, Psychiatry and Brain Research 5, 209212
221Howard, J. and Pilkington, G.J. (1992) Fibronectin staining detects micro-organisms in aged and Alzheimer's disease brain. Neuroreport 3, 615618
222Fenesy, K.E. (1998) Periodontal disease: an overview for physicians. Mount Sinai Journal of Medicine 65, 362369
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, 181191
224Malaguarnera, M. et al. (2004) Helicobacter pylori and Alzheimer's disease: a possible link. European Journal of Internal Medicine 15, 381386
225Kountouras, J. et al. (2006) Relationship between Helicobacter pylori infection and Alzheimer disease. Neurology 66, 938940
226Kountouras, J. et al. (2009) Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer's disease. International Journal of Neuroscience 119, 765777
227Kountouras, J. et al. (2007) Association between Helicobacter pylori infection and mild cognitive impairment. European Journal of Neurology 14, 976982
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, 365368
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, 201208
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, 964973
231Sequiera, L.W. et al. (1979) Detection of herpes-simplex viral genome in brain tissue. Lancet 2, 609612
232Middleton, P.J. et al. (1980) Herpes-simplex viral genome and senile and presenile dementias of Alzheimer and Pick. Lancet 1, 1038
233Pogo, B.G. and Elizan, T.S. (1985) Search for viral DNA sequences in Alzheimer brain tissue. Lancet 1, 978979
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, 907915
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, 123131
236Itzhaki, R.F. et al. (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet 349, 241244
237Itabashi, S. et al. (1997) Herpes simplex virus and risk of Alzheimer's disease. Lancet 349, 1102
238Lin, W.R. et al. (1998) Alzheimer's disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimer's Reports 1, 173178
239Beffert, U. et al. (1998) HSV-1 in brain and risk of Alzheimer's disease. Lancet 351, 13301331
240Beffert, U. et al. (1998) Herpes simplex virus type 1 in brain, apolipoprotein E genotype and Alzheimer's disease. McGill Journal of Medicine 4, 48
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, 131138
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, 300306
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, 311314
244Ounanian, A. et al. (1990) Antibodies to viral antigens, xenoantigens, and autoantigens in Alzheimer's disease. Journal of Clinical Laboratory Analysis 4, 367375
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, 3637
246Lin, W.R. et al. (2002) Herpesviruses in brain and Alzheimer's disease. Journal of Pathology 197, 395402
247Renvoize, E.B. et al. (1979) Possible association of Alzheimer's disease with HLA- BW15 and cytomegalovirus infection. Lancet 1, 1238
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, 10461054
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, 275277
250Igata, T. et al. (1997) Dementia and Borna disease virus. Dementia and Geriatric Cognitive Disorders 9, 2425
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, 696700
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, 255274
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, 19231934
254Rempel, H.C. and Pulliam, L. (2005) HIV-1 Tat inhibits neprilysin and elevates amyloid beta. AIDS (London, England) 19, 127135
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, 379390
256Hook, E.W. III (1989) Syphilis and HIV infection. Journal of Infectious Diseases 160, 530534
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, 720726
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, 294299
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, 53835387
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, 7177
261Miklossy, J. et al. (2006) Beta-amyloid deposition and Alzheimer's type changes induced by Borrelia spirochetes. Neurobiology of Aging 27, 228236
262Little, C.S. et al. (2004) Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiology of Aging 25, 419429
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, Bologna
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, 59885994
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, 305318
266Wozniak, M.A. et al. (2007) Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neuroscience Letters 429, 95100
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, 259269
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, 341350
269Leinonen, M. (1993) Pathogenetic mechanisms and epidemiology of Chlamydia pneumoniae. European Heart Journal 14 (Suppl), 5761
270Boggian, I. et al. (2000) Asymptomatic herpes simplex type 1 virus infection of the mouse brain. Journal of Neurovirology 6, 303313
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, 309321
272Fox, A. (1990) Role of bacterial debris in inflammatory diseases of the joint and eye. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica 98, 957968
273Stimpson, S.A. et al. (1986) Arthropathic properties of cell wall polymers from normal flora bacteria. Infection and Immunity 51, 240249
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, 600608
275Palaniyar, N. et al. (2002) Pulmonary innate immune proteins and receptors that interact with gram-positive bacterial ligands. Immunobiology 205, 575594
276Gebbink, M.F. et al. (2005) Amyloids–a functional coat for microorganisms. Nature Reviews. Microbiology 3, 333341
277Hammer, N.D. et al. (2008) Amyloids: friend or foe? Journal of Alzheimer's Disease 13, 407419
278Gophna, U. et al. (2001) Curli fibers mediate internalization of Escherichia coli by eukaryotic cells. Infection and Immunity 69, 26592665
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, 927935
280Olsén, A., Jonsson, A. and Normark, S. (1989) Fibronectin binding mediated by a novel class of surface organelles on Escherichia coli. Nature 338, 652655
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, 443445
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, 661670
283Umemoto, T., Li, M. and Namikawa, I. (1997) Adherence of human oral spirochetes by collagen-binding proteins. Microbiology and Immunology 41, 917923
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, 476480
285Lorenz, E. et al. (2002) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Archives of Internal Medicine 162, 10281032
286Kiechl, S., Wiedermann, C.J. and Willeit, J. (2003) Toll-like receptor 4 and atherogenesis. Annals of Medicine 35, 164171
287Akira, S. and Takeda, K. (2004) Functions of toll-like receptors: lessons from KO mice. Comptes Rendus Biologies 327, 581589
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, 404411
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, 19
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, 987994
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, 54555464
292Schroeder, N.W. et al. (2004) Lipopolysaccharide binding protein binds to triacylated and diacylated lipopeptides and mediates innate immune responses. Journal of Immunology 173, 26832691
293Radolf, J.D. et al. (1995) Characterization of outer membranes isolated from Borrelia burgdorferi, the Lyme disease spirochete. Infection and Immunity 63, 21542163
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, 25392550
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, 34293434
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, 582587
297Van der Goot, F.G.E. (2001) Pore Forming Toxins. Springer Verlag, Berlin
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, 20082021
299Gonzalez, M.R. (2008) Bacterial pore-forming toxins: The (w)hole story ? Cellular and Molecular Life Sciences 65, 493507
300Gekara, N.O. and Weiss, S. (2004) Lipid rafts clustering and signalling by listeriolysin O. Biochemical Society Transactions 32, 712714
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, 37973806
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, 17091722
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, 1346713472
304Pipkin, M.E. and Lieberman, J. (2007) Delivering the kiss of death: Progress on understanding how perforin works. Current Opinion in Immunology 19, 301308
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, 27412746
306Lawrenz, M.B. et al. (2003) Effect of complement component C3 deficiency on experimental Lyme borreliosis in mice. Infection and Immunity 71, 44324440
307Kraiczy, P. et al. (2001) Mechanism of complement resistance of pathogenic Borrelia burgdorferi isolates. International Immunopharmacology 1, 393401
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, 231238
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, 447458
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, 761766
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, 76067610
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, 773783
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, 16051611
314Sheng, J.G. et al. (2000) Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Experimental Neurology 163, 388391
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, 341348
316Li, Y. et al. (2000) Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. Journal of Neuroscience 20, 149155
317Zhu, S.G. et al. (1999) Increased interleukin-1beta converting enzyme expression and activity in Alzheimer disease. Journal of Neuropathology and Experimental Neurology 58, 582587
318Li, Y. et al. (2004) Microglial activation by uptake of fDNA via a scavenger receptor. Journal of Neuroimmunology 147, 5055
319Barger, S.W. and Harmon, A.D. (1997) Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388, 878881
320Tahara, K. et al. (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129, 30063019
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, 18461854
322Kraiczy, P. and Würzner, R. (2006) Complement escape of human pathogenic bacteria by acquisition of complement regulators. Molecular Immunology 43, 3144
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, 32143222
324Rasley, A., Anguita, J. and Marriott, I. (2002) Borrelia burgdorferi induces inflammatory mediator production by murine microglia. Journal of Neuroimmunology 130, 2231
325Hauss-Wegrzyniak, B., Vraniak, P.D. and Wenk, G.L. (2000) LPS-induced neuroinflammatory effects do not recover with time. Neuroreport 11, 17591763
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, 12591265
327Johannsen, L. (1993) Biological properties of bacterial peptidoglycan. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica 101, 337344
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, 45354539
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, 267270
330Weinberg, G. and Miklossy, J. (2008) Iron and infection. Journal of Alzheimer's Diseases 13, 451463
331Griffiths, E. (1991) Iron and bacterial virulence - a brief overview. Biological Methods 4, 713
332Weinberg, E.D. (1992) Iron depletion: a defense against intracellular infection and neoplasia. Life Sciences 50, 12891297
333Griffiths, W.J. et al. (2000) Localization of iron transport and regulatory proteins in human cells. QJM 93, 575587
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, 97130
335Bishop, G.M. et al. (2002) Iron: a pathological mediator of Alzheimer disease? Developmental Neuroscience 24, 184187
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, 3037
337Lirk, P., Hoffmann, G. and Rieder, J. (2002) Inducible nitric oxide synthase – time for reappraisal. Curr Drug Targets – Inflammation and Allergy 1, 89108
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, 606612
339Chakravortty, D. and Hensel, M. (2003) Inducible nitric oxide synthase and control of intracellular bacterial pathogens. Microbes and Infection 5, 621627
340Shiloh, M.U. and Nathan, C.F. (2000) Reactive nitrogen intermediates and the pathogenesis of Salmonella and mycobacteria. Current Opinion in Microbiology 3, 3542
341Bogdan, C. (2001) Nitric oxide and the immune response. Nature Immunology 2, 907916
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, 20832092
343Otzen, D. and Nielsen, P.H. (2008) We find them here, we find them there: functional bacterial amyloid. Cellular and Molecular Life Sciences 65, 910927
344Chapman, M.R. et al. (2002) Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295, 851855
345Larsen, P. et al. (2007) Amyloid adhesins are abundant in natural biofilms. Environmental Microbiology 9, 30773090
346Jordal, P.B. et al. (2009) Widespread abundance of functional bacterial amyloid in Mycolata and other Gram-positive bacteria. Applied and Environmental Microbiology 75, 41014110
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, 2153021539
348Picken, M.M. (2000) The changing concepts of amyloid. Archives of Pathology and Laboratory Medicine 125, 3843
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, 7578
350Miklossy, J. et al. (2010) Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging. 31:15031515
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, 88438853
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, 290298
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, 196204
354Roy, S. et al. (1997) Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. Journal of Infectious Diseases 176, 530532
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, 187191
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, 21923
357Lagrange, P.H. and Abel, L. (1996) The genetic susceptibility to leprosy in humans. Acta Leprologica 10, 1127
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, 823830
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, 436439
360Gnjec, A. et al. (2008) Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease. Journal of Neuroinflammation 5, 36
361Alves, C. et al. (2007) The role of the human histocompatibility antigens in the pathogenesis of neurological disorders. Revista de Neurologia 44, 298302
362Ballerini, C. et al. (1999) HLA A2 allele is associated with age at onset of Alzheimer's disease. Annals of Neurology 45, 397400
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, 276281
364Nicoll, J.A. et al. (2000) Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Annals of Neurology 47, 365368
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, 147149
366Balistreri, C.R. et al. (2008) Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer's disease. Current Pharmaceutical Design 14, 26722677
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, 421435
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, 16371643
369Corder, E.H. et al. (1998) HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nature Medicine 4, 11821184
370Itzhaki, R.F. et al. (2004) Infiltration of the brain by pathogens causes Alzheimer's disease. Neurobiology of Aging 25, 619627
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, 7390
372Bhattacharjee, P.S. et al. (2008) Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1. Experimental Eye Research 87, 122130
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, 8384
374Perry, V.H., Cunningham, C. and Holmes, C. (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nature Reviews. Immunology 7, 161167
375Perry, V.H., Nicoll, J.A. and Holmes, C. (2010) Microglia in neurodegenerative disease. Nature Reviews. Neurology 6, 193201
376Holmes, C. and Cotterell, D. (2009) Role of infection in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs 23, 9931002
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, 9297
378Blatz, R. et al. (2005) Neurosyphilis and neuroborreliosis. Retrospective evaluation of 22 cases. Der Nervenarzt 76, 724732
379Bolintineanu, D. et al. (2009) Antimicrobial mechanism of pore-forming protegrin peptides: 100 pores to kill E. coli. Peptides 31, 18
380Kobayashi, N. et al. (2008) Binding sites on tau proteins as components for antimicrobial peptides. Biocontrol Science 13, 4956
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, 15951604