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This new perspective on AD amyloidosis seeks to provide a rational framework for incorporating recent and seemingly independent findings on the antimicrobial role of \u03b2\u2010amyloid and emerging experimental, genetic, and epidemiological data, suggesting innate immune\u2010mediated inflammation propagates AD neurodegeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>AD pathology is characterized by cerebral deposition of amyloid\u2010\u03b2 protein (A\u03b2) as \u03b2\u2010amyloid. Genetic studies have confirmed the key role of A\u03b2 in AD, revealing that mutation\u2010mediated shifts in the peptides generation lead to early onset familial Alzheimer's disease. However, A\u03b2 generation appears normal for the majority of AD patients, who lack early onset familial Alzheimer's disease mutations. In prevailing models of nonfamilial AD, individual genetics and age\u2010associated changes in brain milieu promote an intrinsically abnormal propensity of A\u03b2 for self\u2010association. However, emerging findings are increasingly inconsistent with characterization of A\u03b2 oligomerization as a nonphysiological and exclusively pathological activity. Recent studies suggest A\u03b2 is an ancient, highly conserved effector molecule of innate immunity. Moreover, A\u03b2 oligomerization and \u03b2\u2010amyloid generation appear to be important innate immune pathways that mediate pathogen entrapment and protect against infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>New AD amyloidogenesis model<\/jats:title>\n                    <jats:p>Recent findings on inflammation\u2010mediated neurodegeneration and the role of A\u03b2 in immunity have led to emergence of the \u201cAntimicrobial Protection Hypothesis\u201d of AD. In this model, \u03b2\u2010amyloid deposition is an early innate immune response to genuine, or mistakenly perceived, immunochallenge. A\u03b2 first entraps and neutralizes invading pathogens in \u03b2\u2010amyloid. A\u03b2 fibrillization drives neuroinflammatory pathways that help fight the infection and clear \u03b2\u2010amyloid\/pathogen deposits. In AD, chronic activation of this pathway leads to sustained inflammation and neurodegeneration. Mounting data link elevated brain microbe levels with AD. The Antimicrobial Protection Hypothesis reveals how increased brain microbial burden may directly exacerbate \u03b2\u2010amyloid deposition, inflammation, and AD progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Amyloid cascade hypothesis<\/jats:title>\n                    <jats:p>In the antimicrobial protection model, the modality of A\u03b2's pathophysiology is shifted from abnormal stochastic behavior toward dysregulated innate immune response. However, \u03b2\u2010amyloid deposition in AD still leads to neurodegeneration. Thus, the new model extends but remains broadly consistent with the Amyloid Cascade Hypothesis and overwhelming data showing the primacy of A\u03b2 in AD pathology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1016\/j.jalz.2018.06.3040","type":"journal-article","created":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T10:55:33Z","timestamp":1539082533000},"page":"1602-1614","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":462,"title":["The antimicrobial protection hypothesis of Alzheimer's disease"],"prefix":"10.1002","volume":"14","author":[{"given":"Robert D.","family":"Moir","sequence":"first","affiliation":[{"name":"Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Department of Neurology Massachusetts General Hospital and Harvard Medical School Charlestown MA 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