Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer’s disease –conformist, nonconformist, and realistic prospects for AD pathogenesis (original) (raw)

References

1. Alzheimer’s Association. 2018 Alzheimer’s disease facts and figures. Alzheimers Dement. 2018;14:367–429.
   Article Google Scholar
2. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–66.
   Article CAS PubMed Google Scholar
3. Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol. 2018;25:59–70.
   Article CAS PubMed Google Scholar
4. Mattsson N, Schott JM, Hardy J, Turner MR, Zetterberg H. Selective vulnerability in neurodegeneration: insights from clinical variants of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2016;87:1000–4.
   Article PubMed Google Scholar
5. Raskin J, Cummings J, Hardy J, Schuh K, Dean RA. Neurobiology of Alzheimer’s Disease: integrated molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions. Curr Alzheimer Res. 2015;12:712–22.
   Article CAS PubMed PubMed Central Google Scholar
6. Fiest KM, Roberts JI, Maxwell CJ, Hogan DB, Smith EE, Frolkis A, Cohen A, Kirk A, Pearson D, Pringsheim T, Venegas-Torres A, Jette N. The prevalence and incidence of dementia due to Alzheimer’s Disease: a systematic review and meta-analysis. Can J Neurol Sci. 2016;43(Suppl 1):S51–82.
   Article PubMed Google Scholar
7. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R, Contributors. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–62.
   Article PubMed PubMed Central Google Scholar
8. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734–46.
   Article PubMed Google Scholar
9. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–9.
   Article PubMed PubMed Central Google Scholar
10. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–9.
    Article PubMed PubMed Central Google Scholar
11. Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791–800.
    Article PubMed Google Scholar
12. Serrano-Pozo A, Qian J, Muzikansky A, Monsell SE, Montine TJ, Frosch MP, Betensky RA, Hyman BT. Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer Disease continuum. J Neuropathol Exp Neurol. 2016;75:516–26.
    Article CAS PubMed PubMed Central Google Scholar
13. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.
    Article CAS PubMed Google Scholar
14. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18:351–7.
    Article CAS PubMed Google Scholar
15. Braak H, Del Tredici K. Spreading of tau pathology in sporadic Alzheimer’s Disease along Cortico-cortical top-down connections. Cereb Cortex. 2018;28:3372–84.
    Article PubMed PubMed Central Google Scholar
16. Montine TJ, Monsell SE, Beach TG, Bigio EH, Bu Y, Cairns NJ, Frosch M, Henriksen J, Kofler J, Kukull WA, Lee EB, Nelson PT, Schantz AM, Schneider JA, Sonnen JA, Trojanowski JQ, Vinters HV, Zhou XH, Hyman BT. Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer’s disease. Alzheimers Dement. 2016;12:164–9.
    Article PubMed Google Scholar
17. Lagarde J, Sarazin M, Bottlaender M. In vivo PET imaging of neuroinflammation in Alzheimer’s disease. J Neural Transm (Vienna). 2018;125:847–67.
    Article CAS Google Scholar
18. Veitch DP, Weiner MW, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR Jr, Jagust W, Morris JC, Petersen RC, Saykin AJ, Shaw LM, Toga AW, Trojanowski JQ, Alzheimer’s Disease Neuroimaging I. Understanding disease progression and improving Alzheimer’s disease clinical trials: recent highlights from the Alzheimer’s Disease Neuroimaging initiative. Alzheimers Dement. 2018. https://doi.org/10.1016/j.jalz.2018.08.005.
19. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR Jr, Jagust W, Morris JC, Petersen RC, Saykin AJ, Shaw LM, Toga AW, Trojanowski JQ, Alzheimer’s Disease Neuroimaging Initiative. Recent publications from the Alzheimer’s Disease Neuroimaging initiative: reviewing progress toward improved AD clinical trials. Alzheimers Dement. 2017;13:e1–e85.
    Article PubMed PubMed Central Google Scholar
20. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR Jr, Jagust W, Morris JC, Petersen RC, Salazar J, Saykin AJ, Shaw LM, Toga AW, Trojanowski JQ, Alzheimer’s Disease Neuroimaging Initiative. The Alzheimer’s Disease Neuroimaging initiative 3: continued innovation for clinical trial improvement. Alzheimers Dement. 2017;13:561–71.
    Article PubMed Google Scholar
21. Rathore S, Habes M, Iftikhar MA, Shacklett A, Davatzikos C. A review on neuroimaging-based classification studies and associated feature extraction methods for Alzheimer’s disease and its prodromal stages. Neuroimage. 2017;155:530–48.
    Article PubMed Google Scholar
22. Villemagne VL, Chetelat G. Neuroimaging biomarkers in Alzheimer’s disease and other dementias. Ageing Res Rev. 2016;30:4–16.
    Article PubMed Google Scholar
23. Paraskevaidi M, Morais CLM, Freitas DLD, Lima KMG, Mann DMA, Allsop D, Martin-Hirsch PL, Martin FL. Blood-based near-infrared spectroscopy for the rapid low-cost detection of Alzheimer’s disease. Analyst. 2018.
24. Tatebe H, Kasai T, Ohmichi T, Kishi Y, Kakeya T, Waragai M, Kondo M, Allsop D, Tokuda T. Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer’s disease and Down syndrome. Mol Neurodegener. 2017;12:63.
    Article PubMed PubMed Central CAS Google Scholar
25. Jaeger PA, Lucin KM, Britschgi M, Vardarajan B, Huang RP, Kirby ED, Abbey R, Boeve BF, Boxer AL, Farrer LA, Finch N, Graff-Radford NR, Head E, Hoffree M, Huang R, Johns H, Karydas A, Knopman DS, Loboda A, Masliah E, Narasimhan R, Petersen RC, Podtelezhnikov A, Pradhan S, Rademakers R, Sun CH, Younkin SG, Miller BL, Ideker T, Wyss-Coray T. Network-driven plasma proteomics expose molecular changes in the Alzheimer’s brain. Mol Neurodegener. 2016;11:31.
    Article PubMed PubMed Central CAS Google Scholar
26. Blennow K, Zetterberg H. Biomarkers for Alzheimer disease - current status and prospects for the future. J Intern Med. 2018;284(6):643–63.
    Article CAS PubMed Google Scholar
27. O'Bryant SE, Gupta V, Henriksen K, Edwards M, Jeromin A, Lista S, Bazenet C, Soares H, Lovestone S, Hampel H, Montine T, Blennow K, Foroud T, Carrillo M, Graff-Radford N, Laske C, Breteler M, Shaw L, Trojanowski JQ, Schupf N, Rissman RA, Fagan AM, Oberoi P, Umek R, Weiner MW, Grammas P, Posner H, Martins R, Star B, Groups, B. w. Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer’s disease research. Alzheimers Dement. 2015;11:549–60.
    Article PubMed Google Scholar
28. Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, Holtta M, Rosen C, Olsson C, Strobel G, Wu E, Dakin K, Petzold M, Blennow K, Zetterberg H. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15:673–84.
    Article CAS PubMed Google Scholar
29. Arneric SP, Batrla-Utermann R, Beckett L, Bittner T, Blennow K, Carter L, Dean R, Engelborghs S, Genius J, Gordon MF, Hitchcock J, Kaplow J, Luthman J, Meibach R, Raunig D, Romero K, Samtani MN, Savage M, Shaw L, Stephenson D, Umek RM, Vanderstichele H, Willis B, Yule S. Cerebrospinal fluid biomarkers for Alzheimer’s Disease: A view of the regulatory science qualification landscape from the coalition against major diseases CSF biomarker team. J Alzheimers Dis. 2017;55:19–35.
    Article PubMed Google Scholar
30. Blennow K. A review of fluid biomarkers for Alzheimer’s Disease: Moving from CSF to blood. Neurol Ther. 2017;6:15–24.
    Article PubMed PubMed Central Google Scholar
31. Blennow K, Zetterberg H. The past and the future of Alzheimer’s Disease fluid biomarkers. J Alzheimers Dis. 2018;62:1125–40.
    Article PubMed PubMed Central Google Scholar
32. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280–92.
    Article PubMed PubMed Central Google Scholar
33. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21:383–421.
    Article CAS PubMed PubMed Central Google Scholar
34. Ardura-Fabregat A, Boddeke E, Boza-Serrano A, Brioschi S, Castro-Gomez S, Ceyzeriat K, Dansokho C, Dierkes T, Gelders G, Heneka MT, Hoeijmakers L, Hoffmann A, Iaccarino L, Jahnert S, Kuhbandner K, Landreth G, Lonnemann N, Loschmann PA, McManus RM, Paulus A, Reemst K, Sanchez-Caro JM, Tiberi A, Van der Perren A, Vautheny A, Venegas C, Webers A, Weydt P, Wijasa TS, Xiang X, Yang Y. Targeting Neuroinflammation to treat Alzheimer’s Disease. CNS Drugs. 2017;31:1057–82.
    Article CAS PubMed PubMed Central Google Scholar
35. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.
    Article CAS PubMed PubMed Central Google Scholar
36. Jay TR, von Saucken VE, Landreth GE. TREM2 in neurodegenerative diseases. Mol Neurodegener. 2017;12:56.
    Article PubMed PubMed Central CAS Google Scholar
37. Zhao N, Liu CC, Qiao W, Bu G. Apolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease. Biol Psychiatry. 2018;83:347–57.
    Article CAS PubMed Google Scholar
38. Jiang T, Sun Q, Chen S. Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease. Prog Neurobiol. 2016;147:1–19.
    Article CAS PubMed Google Scholar
39. Paillusson S, Stoica R, Gomez-Suaga P, Lau DHW, Mueller S, Miller T, Miller CCJ. There’s something wrong with my MAM; the ER-mitochondria Axis and neurodegenerative diseases. Trends Neurosci. 2016;39:146–57.
    Article CAS PubMed PubMed Central Google Scholar
40. Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA, Fang EF. Mitophagy and Alzheimer’s Disease: cellular and molecular mechanisms. Trends Neurosci. 2017;40:151–66.
    Article CAS PubMed PubMed Central Google Scholar
41. Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci. 2004;5:347–60.
    Article CAS PubMed Google Scholar
42. Iadecola C. The neurovascular unit coming of age: A journey through neurovascular coupling in health and Disease. Neuron. 2017;96:17–42.
    Article CAS PubMed PubMed Central Google Scholar
43. Padurariu M, Ciobica A, Lefter R, Serban IL, Stefanescu C, Chirita R. The oxidative stress hypothesis in Alzheimer’s disease. Psychiatr Danub. 2013;25:401–9.
    CAS PubMed Google Scholar
44. Pratico D. Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci. 2008;29:609–15.
    Article CAS PubMed Google Scholar
45. Markesbery WR. Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med. 1997;23:134–47.
    Article CAS PubMed Google Scholar
46. Hopperton KE, Mohammad D, Trepanier MO, Giuliano V, Bazinet RP. Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review. Mol Psychiatry. 2018;23:177–98.
    Article CAS PubMed Google Scholar
47. Bloom GS, Lazo JS, Norambuena A. Reduced brain insulin signaling: A seminal process in Alzheimer’s disease pathogenesis. Neuropharmacology. 2018;136:192–5.
    Article CAS PubMed Google Scholar
48. Griffith CM, Eid T, Rose GM, Patrylo PR. Evidence for altered insulin receptor signaling in Alzheimer’s disease. Neuropharmacology. 2018;136:202–15.
    Article CAS PubMed Google Scholar
49. Benedict C, Grillo CA. Insulin resistance as a therapeutic target in the treatment of Alzheimer’s Disease: A state-of-the-art review. Front Neurosci. 2018;12:215.
    Article PubMed PubMed Central Google Scholar
50. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5.
    Article CAS PubMed Google Scholar
51. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci. 2005;8:79–84.
    Article CAS PubMed Google Scholar
52. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007;27:2866–75.
    Article CAS PubMed PubMed Central Google Scholar
53. Li S, Shankar GM, Selkoe DJ. How do soluble oligomers of amyloid beta-protein impair hippocampal synaptic plasticity? Front Cell Neurosci. 2010;4:5.
    PubMed PubMed Central Google Scholar
54. Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ. Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci. 2011;31:6627–38.
    Article CAS PubMed PubMed Central Google Scholar
55. Mucke L, Selkoe DJ. Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med. 2012;2:a006338.
    Article PubMed PubMed Central CAS Google Scholar
56. Tu S, Okamoto S, Lipton SA, Xu H. Oligomeric Abeta-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener. 2014;9:48.
    Article PubMed PubMed Central CAS Google Scholar
57. Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and ’wingmen’. Nat Neurosci. 2015;18:800–6.
    Article CAS PubMed PubMed Central Google Scholar
58. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608.
    Article CAS PubMed PubMed Central Google Scholar
59. Du X, Wang X, Geng M. Alzheimer’s disease hypothesis and related therapies. Transl Neurodegener. 2018;7:2.
    Article PubMed PubMed Central Google Scholar
60. Morris GP, Clark IA, Vissel B. Questions concerning the role of amyloid-beta in the definition, aetiology and diagnosis of Alzheimer’s disease. Acta Neuropathol. 2018;136:663–89.
    Article CAS PubMed PubMed Central Google Scholar
61. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398:513–7.
    Article CAS PubMed Google Scholar
62. Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer’s disease. Lancet Neurol. 2013;12:92–104.
    Article CAS PubMed Google Scholar
63. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387–90.
    Article PubMed CAS Google Scholar
64. Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA, Windisch M, Xiong C. Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res Ther. 2011;3:1.
    Article PubMed PubMed Central Google Scholar
65. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774.
    Article CAS PubMed PubMed Central Google Scholar
66. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med. 2011;3:89ra57.
    Article CAS PubMed PubMed Central Google Scholar
67. Hu J, Liu CC, Chen XF, Zhang YW, Xu H, Bu G. Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Abeta metabolism in apoE4-targeted replacement mice. Mol Neurodegener. 2015;10:6.
    Article PubMed PubMed Central CAS Google Scholar
68. Liu CC, Zhao N, Fu Y, Wang N, Linares C, Tsai CW, Bu G. ApoE4 accelerates early seeding of amyloid pathology. Neuron. 2017;96:1024–32 e1023.
    Article CAS PubMed PubMed Central Google Scholar
69. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80.
    Article CAS PubMed Google Scholar
70. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998;95:6448–53.
    Article CAS PubMed PubMed Central Google Scholar
71. Forner S, Baglietto-Vargas D, Martini AC, Trujillo-Estrada L, LaFerla FM. Synaptic impairment in Alzheimer’s Disease: A dysregulated symphony. Trends Neurosci. 2017;40:347–57.
    Article CAS PubMed Google Scholar
72. Audrain M, Fol R, Dutar P, Potier B, Billard JM, Flament J, Alves S, Burlot MA, Dufayet-Chaffaud G, Bemelmans AP, Valette J, Hantraye P, Deglon N, Cartier N, Braudeau J. Alzheimer’s disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression. Mol Neurodegener. 2016;11:5.
    Article PubMed PubMed Central CAS Google Scholar
73. Abramov AY, Canevari L, Duchen MR. Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture. Biochim Biophys Acta. 2004;1742:81–7.
    Article CAS PubMed Google Scholar
74. Canevari L, Abramov AY, Duchen MR. Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochem Res. 2004;29:637–50.
    Article CAS PubMed Google Scholar
75. Camandola S, Mattson MP. Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease. Biochim Biophys Acta. 2011;1813:965–73.
    Article CAS PubMed Google Scholar
76. Mattson MP. ER calcium and Alzheimer’s disease: in a state of flux. Sci Signal. 2010;3:pe10.
    Article PubMed PubMed Central CAS Google Scholar
77. Ferrarelli LK. New connections: amyloid-beta, calcium, and the synapse. Sci Signal. 2017;10.
78. Arbel-Ornath M, Hudry E, Boivin JR, Hashimoto T, Takeda S, Kuchibhotla KV, Hou S, Lattarulo CR, Belcher AM, Shakerdge N, Trujillo PB, Muzikansky A, Betensky RA, Hyman BT, Bacskai BJ. Soluble oligomeric amyloid-beta induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. Mol Neurodegener. 2017;12:27.
    Article PubMed PubMed Central CAS Google Scholar
79. Demuro A, Parker I, Stutzmann GE. Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem. 2010;285:12463–8.
    Article CAS PubMed PubMed Central Google Scholar
80. Bai Y, Li M, Zhou Y, Ma L, Qiao Q, Hu W, Li W, Wills ZP, Gan WB. Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer’s disease. Mol Neurodegener. 2017;12:86.
    Article PubMed PubMed Central CAS Google Scholar
81. Hiruma H, Katakura T, Takahashi S, Ichikawa T, Kawakami T. Glutamate and amyloid beta-protein rapidly inhibit fast axonal transport in cultured rat hippocampal neurons by different mechanisms. J Neurosci. 2003;23:8967–77.
    Article CAS PubMed PubMed Central Google Scholar
82. Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S. Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A. 2009;106:5907–12.
    Article CAS PubMed PubMed Central Google Scholar
83. Decker H, Lo KY, Unger SM, Ferreira ST, Silverman MA. Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured hippocampal neurons. J Neurosci. 2010;30:9166–71.
    Article CAS PubMed PubMed Central Google Scholar
84. Deng M, He W, Tan Y, Han H, Hu X, Xia K, Zhang Z, Yan R. Increased expression of reticulon 3 in neurons leads to reduced axonal transport of beta site amyloid precursor protein-cleaving enzyme 1. J Biol Chem. 2013;288:30236–45.
    Article CAS PubMed PubMed Central Google Scholar
85. Choi H, Kim HJ, Kim J, Kim S, Yang J, Lee W, Park Y, Hyeon SJ, Lee DS, Ryu H, Chung J, Mook-Jung I. Increased acetylation of Peroxiredoxin1 by HDAC6 inhibition leads to recovery of Abeta-induced impaired axonal transport. Mol Neurodegener. 2017;12:23.
    Article PubMed PubMed Central CAS Google Scholar
86. Liu RQ, Zhou QH, Ji SR, Zhou Q, Feng D, Wu Y, Sui SF. Membrane localization of beta-amyloid 1-42 in lysosomes: a possible mechanism for lysosome labilization. J Biol Chem. 2010;285:19986–96.
    Article CAS PubMed PubMed Central Google Scholar
87. Volgyi K, Juhasz G, Kovacs Z, Penke B. Dysfunction of endoplasmic reticulum (ER) and mitochondria (MT) in Alzheimer’s Disease: the role of the ER-MT cross-talk. Curr Alzheimer Res. 2015;12:655–72.
    Article CAS PubMed Google Scholar
88. Sun X, Chen WD, Wang YD. Beta-amyloid: the key peptide in the pathogenesis of Alzheimer’s disease. Front Pharmacol. 2015;6:221.
    PubMed PubMed Central Google Scholar
89. Joshi G, Chi Y, Huang Z, Wang Y. Abeta-induced Golgi fragmentation in Alzheimer’s disease enhances Abeta production. Proc Natl Acad Sci U S A. 2014;111:E1230–9.
    Article CAS PubMed PubMed Central Google Scholar
90. Joshi G, Bekier ME 2nd, Wang Y. Golgi fragmentation in Alzheimer’s disease. Front Neurosci. 2015;9:340.
    Article PubMed PubMed Central Google Scholar
91. Sollvander S, Nikitidou E, Brolin R, Soderberg L, Sehlin D, Lannfelt L, Erlandsson A. Accumulation of amyloid-beta by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol Neurodegener. 2016;11:38.
    Article PubMed PubMed Central CAS Google Scholar
92. Butterfield DA, Boyd-Kimball D. Oxidative stress, Amyloid-beta Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease. J Alzheimers Dis. 2018;62:1345–67.
    Article CAS PubMed PubMed Central Google Scholar
93. Willen K, Edgar JR, Hasegawa T, Tanaka N, Futter CE, Gouras GK. Abeta accumulation causes MVB enlargement and is modelled by dominant negative VPS4A. Mol Neurodegener. 2017;12:61.
    Article PubMed PubMed Central CAS Google Scholar
94. Park J, Choi H, Min JS, Kim B, Lee SR, Yun JW, Choi MS, Chang KT, Lee DS. Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells. J Neurochem. 2015;132:687–702.
    Article CAS PubMed Google Scholar
95. Jiang S, Nandy P, Wang W, Ma X, Hsia J, Wang C, Wang Z, Niu M, Siedlak SL, Torres S, Fujioka H, Xu Y, Lee HG, Perry G, Liu J, Zhu X. Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex. Mol Neurodegener. 2018;13:5.
    Article PubMed PubMed Central Google Scholar
96. Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Scholl M, Chiotis K, Thordardottir S, Graff C, Wall A, Langstrom B, Nordberg A. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain. 2016;139:922–36.
    Article PubMed PubMed Central Google Scholar
97. Rodriguez-Vieitez E, Ni R, Gulyas B, Toth M, Haggkvist J, Halldin C, Voytenko L, Marutle A, Nordberg A. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol Imaging. 2015;42:1119–32.
    Article CAS PubMed PubMed Central Google Scholar
98. Pike CJ, Cummings BJ, Monzavi R, Cotman CW. Beta-amyloid-induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer’s disease. Neuroscience. 1994;63:517–31.
    Article CAS PubMed Google Scholar
99. Craft JM, Watterson DM, Van Eldik LJ. Human amyloid beta-induced neuroinflammation is an early event in neurodegeneration. Glia. 2006;53:484–90.
    Article PubMed Google Scholar
100. Cai Z, Hussain MD, Yan LJ. Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci. 2014;124:307–21.
     Article CAS PubMed Google Scholar
101. Futch HS, Croft CL, Truong VQ, Krause EG, Golde TE. Targeting psychologic stress signaling pathways in Alzheimer’s disease. Mol Neurodegener. 2017;12:49.
     Article PubMed PubMed Central CAS Google Scholar
102. Efthymiou AG, Goate AM. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol Neurodegener. 2017;12:43.
     Article PubMed PubMed Central CAS Google Scholar
103. Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, Rainone V, Nemni R, Mancuso R, Clerici M. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener. 2016;11:23.
     Article PubMed PubMed Central CAS Google Scholar
104. Jankowsky JL, Zheng H. Practical considerations for choosing a mouse model of Alzheimer’s disease. Mol Neurodegener. 2017;12:89.
     Article PubMed PubMed Central Google Scholar
105. LaFerla FM, Green KN. Animal models of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2.
106. Guo Q, Wang Z, Li H, Wiese M, Zheng H. APP physiological and pathophysiological functions: insights from animal models. Cell Res. 2012;22:78–89.
     Article CAS PubMed Google Scholar
107. Stancu IC, Vasconcelos B, Terwel D, Dewachter I. Models of beta-amyloid induced tau-pathology: the long and “folded” road to understand the mechanism. Mol Neurodegener. 2014;9:51.
     Article PubMed PubMed Central CAS Google Scholar
108. He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L, Zhang B, Gathagan RJ, Yue C, Dengler C, Stieber A, Nitla M, Coulter DA, Abel T, Brunden KR, Trojanowski JQ, Lee VM. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018;24:29–38.
     Article CAS PubMed Google Scholar
109. Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci. 2013;33:6245–56.
     Article CAS PubMed PubMed Central Google Scholar
110. Forny-Germano L, e Silva NM, Batista AF, Brito-Moreira J, Gralle M, Boehnke SE, Coe BC, Lablans A, Marques SA, Martinez AM, Klein WL, Houzel JC, Ferreira ST, Munoz DP, De Felice FG. Alzheimer’s disease-like pathology induced by amyloid-beta oligomers in nonhuman primates. J Neurosci. 2014;34:13629–43.
     Article PubMed CAS PubMed Central Google Scholar
111. Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D'Avanzo C, Chen H, Hooli B, Asselin C, Muffat J, Klee JB, Zhang C, Wainger BJ, Peitz M, Kovacs DM, Woolf CJ, Wagner SL, Tanzi RE, Kim DY. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. 2014;515:274–8.
     Article CAS PubMed PubMed Central Google Scholar
112. Kim YH, Choi SH, D'Avanzo C, Hebisch M, Sliwinski C, Bylykbashi E, Washicosky KJ, Klee JB, Brustle O, Tanzi RE, Kim DY. A 3D human neural cell culture system for modeling Alzheimer’s disease. Nat Protoc. 2015;10:985–1006.
     Article CAS PubMed PubMed Central Google Scholar
113. Choi SH, Kim YH, Quinti L, Tanzi RE, Kim DY. 3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”. Mol Neurodegener. 2016;11:75.
     Article PubMed PubMed Central CAS Google Scholar
114. Yang J, Li S, He XB, Cheng C, Le W. Induced pluripotent stem cells in Alzheimer’s disease: applications for disease modeling and cell-replacement therapy. Mol Neurodegener. 2016;11:39.
     Article PubMed PubMed Central CAS Google Scholar
115. Espuny-Camacho I, Arranz AM, Fiers M, Snellinx A, Ando K, Munck S, Bonnefont J, Lambot L, Corthout N, Omodho L, Eynden EV, Radaelli E, Tesseur I, Wray S, Ebneth A, Hardy J, Leroy K, Brion JP, Vanderhaeghen P, De Strooper B. Hallmarks of Alzheimer’s Disease in stem-cell-derived human neurons transplanted into mouse brain. Neuron. 2017;93:1066.
     Article CAS PubMed Google Scholar
116. Ricciarelli R, Fedele E. The amyloid Cascade hypothesis in Alzheimer’s Disease: It’s time to change our mind. Curr Neuropharmacol. 2017;15:926–35.
     Article CAS PubMed PubMed Central Google Scholar
117. Karran E, De Strooper B. The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem. 2016;139(Suppl 2):237–52.
     Article CAS PubMed Google Scholar
118. Harrison JR, Owen MJ. Alzheimer’s disease: the amyloid hypothesis on trial. Br J Psychiatry. 2016;208:1–3.
     Article PubMed Google Scholar
119. Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000;283:1571–7.
     Article CAS PubMed Google Scholar
120. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42:631–9.
     Article CAS PubMed Google Scholar
121. Rodrigue KM, Kennedy KM, Devous MD Sr, Rieck JR, Hebrank AC, Diaz-Arrastia R, Mathews D, Park DC. Beta-amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology. 2012;78:387–95.
     Article CAS PubMed PubMed Central Google Scholar
122. Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X, Peck A. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988;23:138–44.
     Article CAS PubMed Google Scholar
123. Dickson DW, Crystal HA, Mattiace LA, Masur DM, Blau AD, Davies P, Yen SH, Aronson MK. Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging. 1992;13:179–89.
     Article CAS PubMed Google Scholar
124. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65:1509–17.
     Article PubMed PubMed Central Google Scholar
125. Josephs KA, Whitwell JL, Ahmed Z, Shiung MM, Weigand SD, Knopman DS, Boeve BF, Parisi JE, Petersen RC, Dickson DW, Jack CR Jr. Beta-amyloid burden is not associated with rates of brain atrophy. Ann Neurol. 2008;63:204–12.
     Article PubMed PubMed Central Google Scholar
126. Murray ME, Dickson DW. Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer’s disease? Alzheimers Res Ther. 2014;6:24.
     Article PubMed PubMed Central Google Scholar
127. Cummings J, Lee G, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement (N Y). 2018;4:195–214.
     Google Scholar
128. Cummings J. Lessons learned from Alzheimer Disease: clinical trials with negative outcomes. Clin Transl Sci. 2018;11:147–52.
     Article PubMed Google Scholar
129. Walsh DM, Selkoe DJ. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci. 2016;17:251–60.
     Article CAS PubMed PubMed Central Google Scholar
130. Selkoe DJ. The therapeutics of Alzheimer’s disease: where we stand and where we are heading. Ann Neurol. 2013;74:328–36.
     Article CAS PubMed Google Scholar
131. Malek-Ahmadi M, Perez SE, Chen K, Mufson EJ. Neuritic and diffuse plaque associations with memory in non-cognitively impaired elderly. J Alzheimers Dis. 2016;53:1641–52.
     Article CAS PubMed PubMed Central Google Scholar
132. Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology. 2004;62:1984–9.
     Article CAS PubMed Google Scholar
133. Duyckaerts C, Colle MA, Dessi F, Piette F, Hauw JJ. Progression of Alzheimer histopathological changes. Acta Neurol Belg. 1998;98:180–5.
     CAS PubMed Google Scholar
134. Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, Morrison JH, Gold G, Hof PR. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60:1495–500.
     Article CAS PubMed Google Scholar
135. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62:925–31.
     Article CAS PubMed Google Scholar
136. Sarazin M, Lagarde J, Bottlaender M. Distinct tau PET imaging patterns in typical and atypical Alzheimer’s disease. Brain. 2016;139:1321–4.
     Article PubMed Google Scholar
137. Thal DR, Vandenberghe R. Monitoring the progression of Alzheimer’s disease with tau-PET. Brain. 2016;139:1318–20.
     Article PubMed Google Scholar
138. Ossenkoppele R, Schonhaut DR, Scholl M, Lockhart SN, Ayakta N, Baker SL, O'Neil JP, Janabi M, Lazaris A, Cantwell A, Vogel J, Santos M, Miller ZA, Bettcher BM, Vossel KA, Kramer JH, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain. 2016;139:1551–67.
     Article PubMed PubMed Central Google Scholar
139. Scholl M, Lockhart SN, Schonhaut DR, O'Neil JP, Janabi M, Ossenkoppele R, Baker SL, Vogel JW, Faria J, Schwimmer HD, Rabinovici GD, Jagust WJ. PET imaging of tau deposition in the aging human brain. Neuron. 2016;89:971–82.
     Article CAS PubMed PubMed Central Google Scholar
140. Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, Joshi AD, Devous MD Sr, Mintun MS. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain. 2016;139:1539–50.
     Article PubMed Google Scholar
141. Saint-Aubert L, Lemoine L, Chiotis K, Leuzy A, Rodriguez-Vieitez E, Nordberg A. Tau PET imaging: present and future directions. Mol Neurodegener. 2017;12:19.
     Article PubMed PubMed Central CAS Google Scholar
142. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology. 2006;66:1837–44.
     Article CAS PubMed Google Scholar
143. Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009;30:1026–36.
     Article PubMed PubMed Central Google Scholar
144. van Rossum IA, Visser PJ, Knol DL, van der Flier WM, Teunissen CE, Barkhof F, Blankenstein MA, Scheltens P. Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer’s disease. J Alzheimers Dis. 2012;29:319–27.
     Article PubMed CAS Google Scholar
145. van Rossum IA, Vos SJ, Burns L, Knol DL, Scheltens P, Soininen H, Wahlund LO, Hampel H, Tsolaki M, Minthon L, L'Italien G, van der Flier WM, Teunissen CE, Blennow K, Barkhof F, Rueckert D, Wolz R, Verhey F, Visser PJ. Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology. 2012;79:1809–16.
     Article PubMed PubMed Central CAS Google Scholar
146. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002;99:6364–9.
     Article CAS PubMed PubMed Central Google Scholar
147. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science. 2007;316:750–4.
     Article CAS PubMed Google Scholar
148. Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, Dawson HN, Vitek MP, Wade-Martins R, Paulsen O, Vargas-Caballero M. Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci. 2011;31:1688–92.
     Article CAS PubMed PubMed Central Google Scholar
149. DeVos SL, Corjuc BT, Commins C, Dujardin S, Bannon RN, Corjuc D, Moore BD, Bennett RE, Jorfi M, Gonzales JA, Dooley PM, Roe AD, Pitstick R, Irimia D, Frosch MP, Carlson GA, Hyman BT. Tau reduction in the presence of amyloid-beta prevents tau pathology and neuronal death in vivo. Brain. 2018;141:2194–212.
     Article PubMed PubMed Central Google Scholar
150. DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T, Tran H, Nichols B, Zanardi TA, Kordasiewicz HB, Swayze EE, Bennett CF, Diamond MI, Miller TM. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9.
151. Vossel KA, Xu JC, Fomenko V, Miyamoto T, Suberbielle E, Knox JA, Ho K, Kim DH, Yu GQ, Mucke L. Tau reduction prevents Abeta-induced axonal transport deficits by blocking activation of GSK3beta. J Cell Biol. 2015;209:419–33.
     Article CAS PubMed PubMed Central Google Scholar
152. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010;142:387–97.
153. Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, Cui B, Mucke L. Tau reduction prevents Abeta-induced defects in axonal transport. Science. 2010;330:198.
     Article CAS PubMed PubMed Central Google Scholar
154. Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17:5–21.
     Article PubMed CAS Google Scholar
155. Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol. 2013;12:609–22.
     Article CAS PubMed Google Scholar
156. Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I. Mechanisms of tau-induced neurodegeneration. Acta Neuropathol. 2009;118:53–69.
     Article CAS PubMed PubMed Central Google Scholar
157. Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol. 2017;133:665–704.
     Article CAS PubMed PubMed Central Google Scholar
158. Morris M, Knudsen GM, Maeda S, Trinidad JC, Ioanoviciu A, Burlingame AL, Mucke L. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci. 2015;18:1183–9.
     Article CAS PubMed PubMed Central Google Scholar
159. Wu XL, Pina-Crespo J, Zhang YW, Chen XC, Xu HX. Tau-mediated neurodegeneration and potential implications in diagnosis and treatment of Alzheimer’s Disease. Chin Med J. 2017;130:2978–90.
     Article PubMed PubMed Central Google Scholar
160. Sotiropoulos I, Galas MC, Silva JM, Skoulakis E, Wegmann S, Maina MB, Blum D, Sayas CL, Mandelkow EM, Mandelkow E, Spillantini MG, Sousa N, Avila J, Medina M, Mudher A, Buee L. Atypical, non-standard functions of the microtubule associated tau protein. Acta Neuropathol Commun. 2017;5:91.
     Article PubMed PubMed Central CAS Google Scholar
161. Pooler AM, Noble W, Hanger DP. A role for tau at the synapse in Alzheimer’s disease pathogenesis. Neuropharmacology. 2014;76(Pt A):1–8.
     Article CAS PubMed Google Scholar
162. Violet M, Chauderlier A, Delattre L, Tardivel M, Chouala MS, Sultan A, Marciniak E, Humez S, Binder L, Kayed R, Lefebvre B, Bonnefoy E, Buee L, Galas MC. Prefibrillar tau oligomers alter the nucleic acid protective function of tau in hippocampal neurons in vivo. Neurobiol Dis. 2015;82:540–51.
     Article CAS PubMed Google Scholar
163. Sultan A, Nesslany F, Violet M, Begard S, Loyens A, Talahari S, Mansuroglu Z, Marzin D, Sergeant N, Humez S, Colin M, Bonnefoy E, Buee L, Galas MC. Nuclear tau, a key player in neuronal DNA protection. J Biol Chem. 2011;286:4566–75.
     Article CAS PubMed Google Scholar
164. Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Cook C, Miller SJ, Dujardin S, Amaral AS, Grima JC, Bennett RE, Tepper K, DeTure M, Vanderburgh CR, Corjuc BT, DeVos SL, Gonzalez JA, Chew J, Vidensky S, Gage FH, Mertens J, Troncoso J, Mandelkow E, Salvatella X, Lim RYH, Petrucelli L, Wegmann S, Rothstein JD, Hyman BT. Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s Disease. Neuron. 2018;99:925–40 e927.
     Article CAS PubMed PubMed Central Google Scholar
165. Hu W, Zhang X, Tung YC, Xie S, Liu F, Iqbal K. Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement. 2016;12:1066–77.
     Article PubMed Google Scholar
166. Gong CX, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem. 2008;15:2321–8.
     Article CAS PubMed PubMed Central Google Scholar
167. Mazanetz MP, Fischer PM. Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discov. 2007;6:464–79.
     Article CAS PubMed Google Scholar
168. Cook C, Stankowski JN, Carlomagno Y, Stetler C, Petrucelli L. Acetylation: a new key to unlock tau’s role in neurodegeneration. Alzheimers Res Ther. 2014;6:29.
     Article PubMed PubMed Central Google Scholar
169. Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, Sohn PD, Schilling B, Cong X, Ellerby L, Gibson BW, Johnson J, Krogan N, Shamloo M, Gestwicki J, Masliah E, Verdin E, Gan L. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015;21:1154–62.
     Article CAS PubMed PubMed Central Google Scholar
170. Tracy TE, Gan L. Acetylated tau in Alzheimer’s disease: An instigator of synaptic dysfunction underlying memory loss: Increased levels of acetylated tau blocks the postsynaptic signaling required for plasticity and promotes memory deficits associated with tauopathy. Bioessays. 2017;39.
171. Park S, Lee JH, Jeon JH, Lee MJ. Degradation or aggregation: the ramifications of post-translational modifications on tau. BMB Rep. 2018;51:265–73.
     Article CAS PubMed PubMed Central Google Scholar
172. Gong CX, Liu F, Iqbal K. O-GlcNAcylation: A regulator of tau pathology and neurodegeneration. Alzheimers Dement. 2016;12:1078–89.
     Article PubMed Google Scholar
173. Zheng BW, Yang L, Dai XL, Jiang ZF, Huang HC. Roles of O-GlcNAcylation on amyloid-beta precursor protein processing, tau phosphorylation, and hippocampal synapses dysfunction in Alzheimer’s disease. Neurol Res. 2016;38:177–86.
     Article PubMed CAS Google Scholar
174. Hastings NB, Wang X, Song L, Butts BD, Grotz D, Hargreaves R, Fred Hess J, Hong KK, Huang CR, Hyde L, Laverty M, Lee J, Levitan D, Lu SX, Maguire M, Mahadomrongkul V, McEachern EJ, Ouyang X, Rosahl TW, Selnick H, Stanton M, Terracina G, Vocadlo DJ, Wang G, Duffy JL, Parker EM, Zhang L. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener. 2017;12:39.
     Article PubMed PubMed Central CAS Google Scholar
175. Sohn PD, Tracy TE, Son HI, Zhou Y, Leite RE, Miller BL, Seeley WW, Grinberg LT, Gan L. Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment. Mol Neurodegener. 2016;11:47.
     Article PubMed PubMed Central CAS Google Scholar
176. Wang YP, Biernat J, Pickhardt M, Mandelkow E, Mandelkow EM. Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc Natl Acad Sci U S A. 2007;104:10252–7.
     Article CAS PubMed PubMed Central Google Scholar
177. Wang Y, Garg S, Mandelkow EM, Mandelkow E. Proteolytic processing of tau. Biochem Soc Trans. 2010;38:955–61.
     Article CAS PubMed Google Scholar
178. de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL, Hyman BT. Caspase activation precedes and leads to tangles. Nature. 2010;464:1201–4.
     Article PubMed PubMed Central CAS Google Scholar
179. Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, Seyfried NT, Hu WT, Liu Z, Wang JZ, Cheng L, Sun YE, Yu SP, Levey AI, Ye K. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med. 2014;20:1254–62.
     Article CAS PubMed PubMed Central Google Scholar
180. Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B, Hardy J, Hutton M. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet. 2004;13:703–14.
     Article CAS PubMed Google Scholar
181. Cripps D, Thomas SN, Jeng Y, Yang F, Davies P, Yang AJ. Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J Biol Chem. 2006;281:10825–38.
     Article CAS PubMed Google Scholar
182. Luo HB, Xia YY, Shu XJ, Liu ZC, Feng Y, Liu XH, Yu G, Yin G, Xiong YS, Zeng K, Jiang J, Ye K, Wang XC, Wang JZ. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci U S A. 2014;111:16586–91.
     Article CAS PubMed PubMed Central Google Scholar
183. Reynolds MR, Reyes JF, Fu Y, Bigio EH, Guillozet-Bongaarts AL, Berry RW, Binder LI. Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer’s disease and other tauopathies. J Neurosci. 2006;26:10636–45.
     Article CAS PubMed PubMed Central Google Scholar
184. Reyes JF, Fu Y, Vana L, Kanaan NM, Binder LI. Tyrosine nitration within the proline-rich region of tau in Alzheimer’s disease. Am J Pathol. 2011;178:2275–85.
     Article CAS PubMed PubMed Central Google Scholar
185. Reyes JF, Geula C, Vana L, Binder LI. Selective tau tyrosine nitration in non-AD tauopathies. Acta Neuropathol. 2012;123:119–32.
     Article CAS PubMed Google Scholar
186. Chu D, Liu F. Pathological changes of tau related to Alzheimer’s Disease. ACS Chem Neurosci. 2018.
187. Zhou Y, Shi J, Chu D, Hu W, Guan Z, Gong CX, Iqbal K, Liu F. Relevance of phosphorylation and truncation of tau to the Etiopathogenesis of Alzheimer’s Disease. Front Aging Neurosci. 2018;10:27.
     Article PubMed PubMed Central Google Scholar
188. Cheng Y, Bai F. The Association of tau with Mitochondrial Dysfunction in Alzheimer’s Disease. Front Neurosci. 2018;12:163.
     Article PubMed PubMed Central Google Scholar
189. Li XC, Hu Y, Wang ZH, Luo Y, Zhang Y, Liu XP, Feng Q, Wang Q, Ye K, Liu GP, Wang JZ. Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins. Sci Rep. 2016;6:24756.
     Article CAS PubMed PubMed Central Google Scholar
190. Kopeikina KJ, Carlson GA, Pitstick R, Ludvigson AE, Peters A, Luebke JI, Koffie RM, Frosch MP, Hyman BT, Spires-Jones TL. Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer’s disease brain. Am J Pathol. 2011;179:2071–82.
     Article CAS PubMed PubMed Central Google Scholar
191. Reddy PH. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res. 2011;1415:136–48.
     Article CAS PubMed PubMed Central Google Scholar
192. Kandimalla R, Manczak M, Fry D, Suneetha Y, Sesaki H, Reddy PH. Reduced dynamin-related protein 1 protects against phosphorylated tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer’s disease. Hum Mol Genet. 2016;25:4881–97.
     CAS PubMed PubMed Central Google Scholar
193. Boehm J. A ’danse macabre’: tau and Fyn in STEP with amyloid beta to facilitate induction of synaptic depression and excitotoxicity. Eur J Neurosci. 2013;37:1925–30.
     Article PubMed Google Scholar
194. Crimins JL, Pooler A, Polydoro M, Luebke JI, Spires-Jones TL. The intersection of amyloid beta and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer’s disease. Ageing Res Rev. 2013;12:757–63.
     Article CAS PubMed PubMed Central Google Scholar
195. Liao D, Miller EC, Teravskis PJ. Tau acts as a mediator for Alzheimer’s disease-related synaptic deficits. Eur J Neurosci. 2014;39:1202–13.
     Article PubMed PubMed Central Google Scholar
196. Miyamoto T, Stein L, Thomas R, Djukic B, Taneja P, Knox J, Vossel K, Mucke L. Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture. Mol Neurodegener. 2017;12:41.
     Article PubMed PubMed Central CAS Google Scholar
197. Talmat-Amar Y, Arribat Y, Parmentier ML. Vesicular Axonal Transport is Modified In Vivo by Tau Deletion or Overexpression in Drosophila. Int J Mol Sci. 2018;19.
198. Lacovich V, Espindola SL, Alloatti M, Pozo Devoto V, Cromberg LE, Carna ME, Forte G, Gallo JM, Bruno L, Stokin GB, Avale ME, Falzone TL. Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons. J Neurosci. 2017;37:58–69.
     Article CAS PubMed PubMed Central Google Scholar
199. Cox K, Combs B, Abdelmesih B, Morfini G, Brady ST, Kanaan NM. Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition. Neurobiol Aging. 2016;47:113–26.
     Article CAS PubMed PubMed Central Google Scholar
200. Rodriguez-Martin T, Cuchillo-Ibanez I, Noble W, Nyenya F, Anderton BH, Hanger DP. Tau phosphorylation affects its axonal transport and degradation. Neurobiol Aging. 2013;34:2146–57.
     Article CAS PubMed PubMed Central Google Scholar
201. Maziuk BF, Apicco DJ, Cruz AL, Jiang L, Ash PEA, da Rocha EL, Zhang C, Yu WH, Leszyk J, Abisambra JF, Li H, Wolozin B. RNA binding proteins co-localize with small tau inclusions in tauopathy. Acta Neuropathol Commun. 2018;6:71.
     Article PubMed PubMed Central Google Scholar
202. Apicco DJ, Ash PEA, Maziuk B, LeBlang C, Medalla M, Al Abdullatif A, Ferragud A, Botelho E, Ballance HI, Dhawan U, Boudeau S, Cruz AL, Kashy D, Wong A, Goldberg LR, Yazdani N, Zhang C, Ung CY, Tripodis Y, Kanaan NM, Ikezu T, Cottone P, Leszyk J, Li H, Luebke J, Bryant CD, Wolozin B. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci. 2018;21:72–80.
     Article CAS PubMed Google Scholar
203. Yoshitake J, Soeda Y, Ida T, Sumioka A, Yoshikawa M, Matsushita K, Akaike T, Takashima A. Modification of TAU by 8-Nitroguanosine 3’,5’-cyclic monophosphate (8-nitro-cGMP): EFFECTS OF NITRIC OXIDE-LINKED CHEMICAL MODIFICATION ON TAU AGGREGATION. J Biol Chem. 2016;291:22714–20.
     Article CAS PubMed PubMed Central Google Scholar
204. Brunello CA, Yan X, Huttunen HJ. Internalized tau sensitizes cells to stress by promoting formation and stability of stress granules. Sci Rep. 2016;6:30498.
     Article CAS PubMed PubMed Central Google Scholar
205. Pallas-Bazarra N, Jurado-Arjona J, Navarrete M, Esteban JA, Hernandez F, Avila J, Llorens-Martin M. Novel function of tau in regulating the effects of external stimuli on adult hippocampal neurogenesis. EMBO J. 2016;35:1417–36.
     Article CAS PubMed PubMed Central Google Scholar
206. Vanderweyde T, Apicco DJ, Youmans-Kidder K, Ash PEA, Cook C, Lummertz da Rocha E, Jansen-West K, Frame AA, Citro A, Leszyk JD, Ivanov P, Abisambra JF, Steffen M, Li H, Petrucelli L, Wolozin B. Interaction of tau with the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity. Cell Rep. 2016;15:1455–66.
     Article CAS PubMed PubMed Central Google Scholar
207. Kohler C. Granulovacuolar degeneration: a neurodegenerative change that accompanies tau pathology. Acta Neuropathol. 2016;132:339–59.
     Article PubMed CAS Google Scholar
208. Wren MC, Zhao J, Liu CC, Murray ME, Atagi Y, Davis MD, Fu Y, Okano HJ, Ogaki K, Strongosky AJ, Tacik P, Rademakers R, Ross OA, Dickson DW, Wszolek ZK, Kanekiyo T, Bu G. Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells. Mol Neurodegener. 2015;10:46.
     Article PubMed PubMed Central CAS Google Scholar
209. Komuro Y, Xu G, Bhaskar K, Lamb BT. Human tau expression reduces adult neurogenesis in a mouse model of tauopathy. Neurobiol Aging. 2015;36:2034–42.
     Article CAS PubMed PubMed Central Google Scholar
210. Joseph M, Anglada-Huguet M, Paesler K, Mandelkow E, Mandelkow EM. Anti-aggregant tau mutant promotes neurogenesis. Mol Neurodegener. 2017;12:88.
     Article PubMed PubMed Central Google Scholar
211. Dioli C, Patricio P, Trindade R, Pinto LG, Silva JM, Morais M, Ferreiro E, Borges S, Mateus-Pinheiro A, Rodrigues AJ, Sousa N, Bessa JM, Pinto L, Sotiropoulos I. Tau-dependent suppression of adult neurogenesis in the stressed hippocampus. Mol Psychiatry. 2017;22:1110–8.
     Article CAS PubMed Google Scholar
212. Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441–68.
     Article CAS PubMed PubMed Central Google Scholar
213. Woodling NS, Andreasson KI. Untangling the web: toxic and protective effects of Neuroinflammation and PGE2 signaling in Alzheimer’s Disease. ACS Chem Neurosci. 2016;7:454–63.
     Article CAS PubMed Google Scholar
214. Labzin LI, Heneka MT, Latz E. Innate immunity and neurodegeneration. Annu Rev Med. 2018;69:437–49.
     Article CAS PubMed Google Scholar
215. Mushegian AA. Harnessing innate immunity to fight neurodegeneration. Sci Signal. 2017;10.
216. Bolos M, Llorens-Martin M, Perea JR, Jurado-Arjona J, Rabano A, Hernandez F, Avila J. Absence of CX3CR1 impairs the internalization of tau by microglia. Mol Neurodegener. 2017;12:59.
     Article PubMed PubMed Central CAS Google Scholar
217. Laurent C, Dorothee G, Hunot S, Martin E, Monnet Y, Duchamp M, Dong Y, Legeron FP, Leboucher A, Burnouf S, Faivre E, Carvalho K, Caillierez R, Zommer N, Demeyer D, Jouy N, Sazdovitch V, Schraen-Maschke S, Delarasse C, Buee L, Blum D. Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain. 2017;140:184–200.
     Article PubMed Google Scholar
218. Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG. Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol. 2004;165:1643–52.
     Article CAS PubMed PubMed Central Google Scholar
219. Leyns CEG, Holtzman DM. Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener. 2017;12:50.
     Article PubMed PubMed Central CAS Google Scholar
220. Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284:12845–52.
     Article CAS PubMed PubMed Central Google Scholar
221. Lewis J, Dickson DW. Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol. 2016;131:27–48.
     Article CAS PubMed Google Scholar
222. Wang Y, Balaji V, Kaniyappan S, Kruger L, Irsen S, Tepper K, Chandupatla R, Maetzler W, Schneider A, Mandelkow E, Mandelkow EM. The release and trans-synaptic transmission of tau via exosomes. Mol Neurodegener. 2017;12:5.
     Article PubMed PubMed Central CAS Google Scholar
223. Goedert M, Eisenberg DS, Crowther RA. Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci. 2017;40:189–210.
     Article CAS PubMed Google Scholar
224. Polanco JC, Scicluna BJ, Hill AF, Gotz J. Extracellular vesicles isolated from the brains of rTg4510 mice seed tau protein aggregation in a threshold-dependent manner. J Biol Chem. 2016;291:12445–66.
     Article CAS PubMed PubMed Central Google Scholar
225. Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol. 2015;129:221–37.
     Article CAS PubMed Google Scholar
226. Xu Y, Martini-Stoica H, Zheng H. A seeding based cellular assay of tauopathy. Mol Neurodegener. 2016;11:32.
     Article PubMed PubMed Central CAS Google Scholar
227. Stanley M, Macauley SL, Holtzman DM. Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? J Exp Med. 2016;213:1375–85.
     Article CAS PubMed PubMed Central Google Scholar
228. Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci. 2015;16:660–71.
     Article CAS PubMed Google Scholar
229. Blazquez E, Velazquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol (Lausanne). 2014;5:161.
     Article Google Scholar
230. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–38.
     Article CAS PubMed PubMed Central Google Scholar
231. Rodriguez-Rodriguez P, Sandebring-Matton A, Merino-Serrais P, Parrado-Fernandez C, Rabano A, Winblad B, Avila J, Ferrer I, Cedazo-Minguez A. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons. Brain. 2017;140:3269–85.
     Article PubMed Google Scholar
232. Gratuze M, Joly-Amado A, Vieau D, Buee L, Blum D. Mutual relationship between tau and central insulin Signalling: consequences for AD and Tauopathies? Neuroendocrinology. 2018;107:181–95.
     Article CAS PubMed Google Scholar
233. Barini E, Antico O, Zhao Y, Asta F, Tucci V, Catelani T, Marotta R, Xu H, Gasparini L. Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol Neurodegener. 2016;11:16.
     Article PubMed PubMed Central CAS Google Scholar
234. Holtzman DM, Carrillo MC, Hendrix JA, Bain LJ, Catafau AM, Gault LM, Goedert M, Mandelkow E, Mandelkow EM, Miller DS, Ostrowitzki S, Polydoro M, Smith S, Wittmann M, Hutton M. Tau: from research to clinical development. Alzheimers Dement. 2016;12:1033–9.
     Article PubMed Google Scholar
235. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998;95:7737–41.
     Article CAS PubMed PubMed Central Google Scholar
236. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702–5.
     Article CAS PubMed Google Scholar
237. Pir GJ, Choudhary B, Mandelkow E, Mandelkow EM. Tau mutant A152T, a risk factor for FTD/PSP, induces neuronal dysfunction and reduced lifespan independently of aggregation in a C. elegans Tauopathy model. Mol Neurodegener. 2016;11:33.
     Article PubMed PubMed Central CAS Google Scholar
238. Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011;121:171–81.
     Article PubMed Google Scholar
239. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70:960–9.
     Article CAS PubMed Google Scholar
240. Zhao N, Liu CC, Van Ingelgom AJ, Linares C, Kurti A, Knight JA, Heckman MG, Diehl NN, Shinohara M, Martens YA, Attrebi ON, Petrucelli L, Fryer JD, Wszolek ZK, Graff-Radford NR, Caselli RJ, Sanchez-Contreras MY, Rademakers R, Murray ME, Koga S, Dickson DW, Ross OA, Bu G. APOE epsilon2 is associated with increased tau pathology in primary tauopathy. Nat Commun. 2018;9:4388.
     Article PubMed PubMed Central CAS Google Scholar
241. Ikeda K, Akiyama H, Arai T, Sahara N, Mori H, Usami M, Sakata M, Mizutani T, Wakabayashi K, Takahashi H. A subset of senile dementia with high incidence of the apolipoprotein E epsilon2 allele. Ann Neurol. 1997;41:693–5.
     Article CAS PubMed Google Scholar
242. Ghebremedhin E, Schultz C, Botez G, Rub U, Sassin I, Braak E, Braak H. Argyrophilic grain disease is associated with apolipoprotein E epsilon 2 allele. Acta Neuropathol. 1998;96:222–4.
     Article CAS PubMed Google Scholar
243. Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, Cairns NJ, Morris JC, Holtzman DM, Fagan AM. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013;12:957–65.
     Article PubMed PubMed Central Google Scholar
244. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosen E, Aarsland D, Visser PJ, Schroder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttila T, Wallin A, Jonhagen ME, Minthon L, Winblad B, Blennow K. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302:385–93.
     Article CAS PubMed Google Scholar
245. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5:228–34.
     Article CAS PubMed Google Scholar
246. Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, Moebius HJ, Bentham P, Kook KA, Wischik DJ, Schelter BO, Davis CS, Staff RT, Bracoud L, Shamsi K, Storey JM, Harrington CR, Wischik CM. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016;388:2873–84.
     Article CAS PubMed PubMed Central Google Scholar
247. Novak P, Schmidt R, Kontsekova E, Zilka N, Kovacech B, Skrabana R, Vince-Kazmerova Z, Katina S, Fialova L, Prcina M, Parrak V, Dal-Bianco P, Brunner M, Staffen W, Rainer M, Ondrus M, Ropele S, Smisek M, Sivak R, Winblad B, Novak M. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16:123–34.
     Article CAS PubMed Google Scholar
248. Medina M. An Overview on the Clinical Development of Tau-Based Therapeutics. Int J Mol Sci. 2018;19.
249. Agadjanyan MG, Zagorski K, Petrushina I, Davtyan H, Kazarian K, Antonenko M, Davis J, Bon C, Blurton-Jones M, Cribbs DH, Ghochikyan A. Humanized monoclonal antibody armanezumab specific to N-terminus of pathological tau: characterization and therapeutic potency. Mol Neurodegener. 2017;12:33.
     Article PubMed PubMed Central CAS Google Scholar
250. Congdon EE, Lin Y, Rajamohamedsait HB, Shamir DB, Krishnaswamy S, Rajamohamedsait WJ, Rasool S, Gonzalez V, Levenga J, Gu J, Hoeffer C, Sigurdsson EM. Affinity of tau antibodies for solubilized pathological tau species but not their immunogen or insoluble tau aggregates predicts in vivo and ex vivo efficacy. Mol Neurodegener. 2016;11:62.
     Article PubMed PubMed Central CAS Google Scholar
251. Ising C, Gallardo G, Leyns CEG, Wong CH, Stewart F, Koscal LJ, Roh J, Robinson GO, Remolina Serrano J, Holtzman DM. AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy. J Exp Med. 2017;214:1227–38.
     Article CAS PubMed PubMed Central Google Scholar
252. West T, Hu Y, Verghese PB, Bateman RJ, Braunstein JB, Fogelman I, Budur K, Florian H, Mendonca N, Holtzman DM. Preclinical and clinical development of ABBV-8E12, a humanized anti-tau antibody, for treatment of Alzheimer’s Disease and other Tauopathies. J Prev Alzheimers Dis. 2017;4:236–41.
     CAS PubMed Google Scholar
253. Yanamandra K, Patel TK, Jiang H, Schindler S, Ulrich JD, Boxer AL, Miller BL, Kerwin DR, Gallardo G, Stewart F, Finn MB, Cairns NJ, Verghese PB, Fogelman I, West T, Braunstein J, Robinson G, Keyser J, Roh J, Knapik SS, Hu Y, Holtzman DM. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci Transl Med. 2017;9.
254. Strang KH, Goodwin MS, Riffe C, Moore BD, Chakrabarty P, Levites Y, Golde TE, Giasson BI. Generation and characterization of new monoclonal antibodies targeting the PHF1 and AT8 epitopes on human tau. Acta Neuropathol Commun. 2017;5:58.
     Article PubMed PubMed Central CAS Google Scholar
255. Jack CR Jr, Wiste HJ, Weigand SD, Therneau TM, Knopman DS, Lowe V, Vemuri P, Mielke MM, Roberts RO, Machulda MM, Senjem ML, Gunter JL, Rocca WA, Petersen RC. Age-specific and sex-specific prevalence of cerebral beta-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50-95 years: a cross-sectional study. Lancet Neurol. 2017;16:435–44.
     Article CAS PubMed PubMed Central Google Scholar
256. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS, Petersen RC, Scheltens P, Sperling RA, Dubois B. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87:539–47.
     Article CAS PubMed PubMed Central Google Scholar
257. Fulop T, Itzhaki RF, Balin BJ, Miklossy J, Barron AE. Role of microbes in the development of Alzheimer’s Disease: state of the art - an international symposium presented at the 2017 IAGG congress in San Francisco. Front Genet. 2018;9:362.
     Article PubMed PubMed Central Google Scholar
258. Doulberis M, Kotronis G, Thomann R, Polyzos SA, Boziki M, Gialamprinou D, Deretzi G, Katsinelos P, Kountouras J. Review: impact of helicobacter pylori on Alzheimer’s disease: what do we know so far? Helicobacter. 2018;23.
259. Harris SA, Harris EA. Molecular mechanisms for herpes simplex virus type 1 pathogenesis in Alzheimer’s Disease. Front Aging Neurosci. 2018;10:48.
     Article PubMed PubMed Central Google Scholar
260. Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, Clerici M, Cosby SL, Del Tredici K, Field H, Fulop T, Grassi C, Griffin WS, Haas J, Hudson AP, Kamer AR, Kell DB, Licastro F, Letenneur L, Lovheim H, Mancuso R, Miklossy J, Otth C, Palamara AT, Perry G, Preston C, Pretorius E, Strandberg T, Tabet N, Taylor-Robinson SD, Whittum-Hudson JA. Microbes and Alzheimer’s Disease. J Alzheimers Dis. 2016;51:979–84.
     Article PubMed PubMed Central Google Scholar
261. Harding A, Gonder U, Robinson SJ, Crean S, Singhrao SK. Exploring the association between Alzheimer’s Disease, Oral Health, Microbial Endocrinology and Nutrition. Front Aging Neurosci. 2017;9:398.
     Article PubMed PubMed Central CAS Google Scholar
262. Kristensson K, Masocha W, Bentivoglio M. Mechanisms of CNS invasion and damage by parasites. Handb Clin Neurol. 2013;114:11–22.
     Article PubMed Google Scholar
263. Dando SJ, Mackay-Sim A, Norton R, Currie BJ, St John JA, Ekberg JA, Batzloff M, Ulett GC, Beacham IR. Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clin Microbiol Rev. 2014;27:691–726.
     Article PubMed PubMed Central CAS Google Scholar
264. Dahm T, Rudolph H, Schwerk C, Schroten H, Tenenbaum T. Neuroinvasion and inflammation in viral central nervous system infections. Mediat Inflamm. 2016;2016:8562805.
     Article CAS Google Scholar
265. Doran KS, Fulde M, Gratz N, Kim BJ, Nau R, Prasadarao N, Schubert-Unkmeir A, Tuomanen EI, Valentin-Weigand P. Host-pathogen interactions in bacterial meningitis. Acta Neuropathol. 2016;131:185–209.
     Article CAS PubMed PubMed Central Google Scholar
266. Miner JJ, Diamond MS. Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier. Curr Opin Immunol. 2016;38:18–23.
     Article CAS PubMed Google Scholar
267. Solomos AC, Rall GF. Get it through your thick Head: emerging principles in Neuroimmunology and Neurovirology redefine central nervous system “immune privilege”. ACS Chem Neurosci. 2016;7:435–41.
     Article CAS PubMed Google Scholar
268. Ball MJ. Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved? Can J Neurol Sci. 1982;9:303–6.
     Article CAS PubMed Google Scholar
269. Itzhaki RF, Wozniak MA, Appelt DM, Balin BJ. Infiltration of the brain by pathogens causes Alzheimer’s disease. Neurobiol Aging. 2004;25:619–27.
     Article CAS PubMed Google Scholar
270. Itzhaki RF. Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Front Aging Neurosci. 2014;6:202.
     Article PubMed PubMed Central CAS Google Scholar
271. Itzhaki RF. Herpes and Alzheimer’s Disease: subversion in the central nervous system and how it might be halted. J Alzheimers Dis. 2016;54:1273–81.
     Article CAS PubMed Google Scholar
272. Itzhaki RF. Herpes simplex virus type 1 and Alzheimer’s disease: possible mechanisms and signposts. FASEB J. 2017;31:3216–26.
     Article CAS PubMed Google Scholar
273. Singhrao SK, Harding A, Simmons T, Robinson S, Kesavalu L, Crean S. Oral inflammation, tooth loss, risk factors, and association with progression of Alzheimer’s disease. J Alzheimers Dis. 2014;42:723–37.
     Article CAS PubMed Google Scholar
274. Gurav A. N. (2014) Alzheimer’s disease and periodontitis--an elusive link. Rev Assoc Med Bras. 1992;60:173–80.
     Article Google Scholar
275. Pritchard AB, Crean S, Olsen I, Singhrao SK. Periodontitis, Microbiomes and their Role in Alzheimer’s Disease. Front Aging Neurosci. 2017;9:336.
     Article CAS PubMed PubMed Central Google Scholar
276. Aguayo S, Schuh C, Vicente B, Aguayo LG. Association between Alzheimer’s Disease and Oral and gut microbiota: are pore forming proteins the missing link? J Alzheimers Dis. 2018;65(1):29–46.
     Article PubMed Google Scholar
277. Fulop T, Witkowski JM, Bourgade K, Khalil A, Zerif E, Larbi A, Hirokawa K, Pawelec G, Bocti C, Lacombe G, Dupuis G, Frost EH. Can an infection hypothesis explain the Beta amyloid hypothesis of Alzheimer’s Disease? Front Aging Neurosci. 2018;10:224.
     Article PubMed PubMed Central Google Scholar
278. Broxmeyer L. Dr. Oskar Fischer’s mysterious little Alzheimer’s germ. J Alzheimers Dis Ed Blog. 2017.
279. Goedert M. Oskar Fischer and the study of dementia. Brain. 2009;132:1102–11.
     Article PubMed Google Scholar
280. Buxbaum JN. Alzheimer’s Disease: It’s more than Abeta. FASEB J. 2017;31:2–4.
     Article CAS PubMed Google Scholar
281. Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Yeh HW, Chiang WS, Chou YC, Tsao CH, Wu YF, Chien WC. Anti-herpetic medications and reduced risk of dementia in patients with herpes simplex virus infections-a Nationwide, Population-Based Cohort Study in Taiwan. Neurotherapeutics. 2018;15:417–29.
     Article PubMed PubMed Central Google Scholar
282. Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, Sano M, Liang WS, Beckmann ND, Price ND, Reiman EM, Schadt EE, Ehrlich ME, Gandy S, Dudley JT. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 2018;99:64–82 e67.
     Article CAS PubMed PubMed Central Google Scholar
283. Chen CK, Wu YT, Chang YC. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther. 2017;9:56.
     Article PubMed PubMed Central Google Scholar
284. Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol. 1991;33:224–7.
     Article CAS PubMed Google Scholar
285. Jamieson GA, Maitland NJ, Craske J, Wilcock GK, Itzhaki RF. Detection of herpes simplex virus type 1 DNA sequences in normal and Alzheimer’s disease brain using polymerase chain reaction. Biochem Soc Trans. 1991;19:122S.
     Article CAS PubMed Google Scholar
286. Jamieson GA, Maitland NJ, Itzhaki RF. Herpes simplex virus type 1 DNA sequences are present in aged normal and Alzheimer’s disease brain but absent in lymphocytes. Arch Gerontol Geriatr. 1992;15(Suppl 1):197–201.
     Article PubMed Google Scholar
287. Itzhaki RF, Lin WR. Herpes simplex virus type I in brain and the type 4 allele of the apolipoprotein E gene are a combined risk factor for Alzheimer’s disease. Biochem Soc Trans. 1998;26:273–7.
     Article CAS PubMed Google Scholar
288. Lin WR, Wozniak MA, Cooper RJ, Wilcock GK, Itzhaki RF. Herpesviruses in brain and Alzheimer’s disease. J Pathol. 2002;197:395–402.
     Article CAS PubMed Google Scholar
289. Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF. Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer’s disease patients. J Med Virol. 2005;75:300–6.
     Article PubMed Google Scholar
290. Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J Pathol. 2009;217:131–8.
     Article CAS PubMed Google Scholar
291. Liedtke W, Opalka B, Zimmermann CW, Lignitz E. Age distribution of latent herpes simplex virus 1 and varicella-zoster virus genome in human nervous tissue. J Neurol Sci. 1993;116:6–11.
     Article CAS PubMed Google Scholar
292. Nicoll JA, Love S, Kinrade E. Distribution of herpes simplex virus DNA in the brains of human long-term survivors of encephalitis. Neurosci Lett. 1993;157:215–8.
     Article CAS PubMed Google Scholar
293. Sanders VJ, Felisan S, Waddell A, Tourtellotte WW. Detection of herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction. J Neuro-Oncol. 1996;2:249–58.
     CAS Google Scholar
294. Sanders VJ, Felisan SL, Waddell AE, Conrad AJ, Schmid P, Swartz BE, Kaufman M, Walsh GO, De Salles AA, Tourtellotte WW. Presence of herpes simplex DNA in surgical tissue from human epileptic seizure foci detected by polymerase chain reaction: preliminary study. Arch Neurol. 1997;54:954–60.
     Article CAS PubMed Google Scholar
295. Beffert U, Bertrand P, Champagne D, Gauthier S, Poirier J. HSV-1 in brain and risk of Alzheimer’s disease. Lancet. 1998;351:1330–1.
     Article CAS PubMed Google Scholar
296. Hemling N, Roytta M, Rinne J, Pollanen P, Broberg E, Tapio V, Vahlberg T, Hukkanen V. Herpesviruses in brains in Alzheimer’s and Parkinson’s diseases. Ann Neurol. 2003;54:267–71.
     Article CAS PubMed Google Scholar
297. Agostini S, Mancuso R, Baglio F, Cabinio M, Hernis A, Guerini FR, Calabrese E, Nemni R, Clerici M. Lack of evidence for a role of HHV-6 in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis. 2016;49:229–35.
     Article PubMed CAS Google Scholar
298. Hill JM, Ball MJ, Neumann DM, Azcuy AM, Bhattacharjee PS, Bouhanik S, Clement C, Lukiw WJ, Foster TP, Kumar M, Kaufman HE, Thompson HW. The high prevalence of herpes simplex virus type 1 DNA in human trigeminal ganglia is not a function of age or gender. J Virol. 2008;82:8230–4.
     Article CAS PubMed PubMed Central Google Scholar
299. Yamazaki Y, Painter MM, Bu G, Kanekiyo T. Apolipoprotein E as a therapeutic target in Alzheimer’s Disease: A review of basic research and clinical evidence. CNS Drugs. 2016;30:773–89.
     Article CAS PubMed PubMed Central Google Scholar
300. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet. 1997;349:241–4.
     Article CAS PubMed Google Scholar
301. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017;7:13537.
     Article PubMed PubMed Central CAS Google Scholar
302. Xu R, Wang Q. Towards understanding brain-gut-microbiome connections in Alzheimer’s disease. BMC Syst Biol. 2016;10(Suppl 3):63.
     Article PubMed PubMed Central CAS Google Scholar
303. MahmoudianDehkordi S, Arnold M, Nho K, Ahmad S, Jia W, Xie G, Louie G, Kueider-Paisley A, Moseley MA, Thompson JW, St John Williams L, Tenenbaum JD, Blach C, Baillie R, Han X, Bhattacharyya S, Toledo JB, Schafferer S, Klein S, Koal T, Risacher SL, Kling MA, Motsinger-Reif A, Rotroff DM, Jack J, Hankemeier T, Bennett DA, De Jager PL, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, van Duijn CM, Saykin AJ, Kastenmuller G, Kaddurah-Daouk R, Alzheimer’s Disease Neuroimaging, I., and the Alzheimer Disease Metabolomics, C. Altered bile acid profile associates with cognitive impairment in Alzheimer’s disease-an emerging role for gut microbiome. Alzheimers Dement. 2018.
304. Kohler CA, Maes M, Slyepchenko A, Berk M, Solmi M, Lanctot KL, Carvalho AF. The gut-brain Axis, Including the Microbiome, Leaky Gut and Bacterial Translocation: Mechanisms and Pathophysiological Role in Alzheimer’s Disease. Curr Pharm Des. 2016;22:6152–66.
     Article CAS PubMed Google Scholar
305. Sochocka M, Donskow-Lysoniewska K, Diniz BS, Kurpas D, Brzozowska E, Leszek J. The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s Disease-a critical review. Mol Neurobiol. 2018.
306. Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, Oyler-Castrillo P, Zhang X, Musch MW, Shen X, Jabri B, Chang EB, Tanzi RE, Sisodia SS. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1DeltaE9 murine model of Alzheimer’s disease. Sci Rep. 2017;7:10411.
     Article PubMed PubMed Central CAS Google Scholar
307. Minter MR, Zhang C, Leone V, Ringus DL, Zhang X, Oyler-Castrillo P, Musch MW, Liao F, Ward JF, Holtzman DM, Chang EB, Tanzi RE, Sisodia SS. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci Rep. 2016;6:30028.
     Article CAS PubMed PubMed Central Google Scholar
308. Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, Neher JJ, Fak F, Jucker M, Lasser T, Bolmont T. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7:41802.
     Article CAS PubMed PubMed Central Google Scholar
309. Ball MJ, Lukiw WJ, Kammerman EM, Hill JM. Intracerebral propagation of Alzheimer’s disease: strengthening evidence of a herpes simplex virus etiology. Alzheimers Dement. 2013;9:169–75.
     Article PubMed Google Scholar
310. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010;5:e9505.
     Article PubMed PubMed Central CAS Google Scholar
311. Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med. 2016;8:340ra372.
     Article CAS Google Scholar
312. Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, Gyorgy B, Breakefield XO, Tanzi RE, Moir RD. Alzheimer’s Disease-associated beta-amyloid is rapidly seeded by Herpesviridae to protect against brain infection. Neuron. 2018;99:56–63 e53.
     Article CAS PubMed PubMed Central Google Scholar
313. White MR, Kandel R, Tripathi S, Condon D, Qi L, Taubenberger J, Hartshorn KL. Alzheimer’s associated beta-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One. 2014;9:e101364.
     Article PubMed PubMed Central Google Scholar
314. Bourgade K, Garneau H, Giroux G, Le Page AY, Bocti C, Dupuis G, Frost EH, Fulop T Jr. Beta-amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology. 2015;16:85–98.
     Article CAS PubMed Google Scholar
315. Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement. 2018;14(12):1602–14.
     Article PubMed Google Scholar
316. Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, Liu CS, Park C, Kennedy G, Long T, Chun J. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature. 2018.

Download references