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While the direct involvement of A\u03b2 in AD has been well documented, the relations between A\u03b2 production, amyloid formation, and neurodegeneration remain unknown. We propose that AD is initiated by a protein aging\u2010related structural transformation in soluble A\u03b2 . We hypothesize that spontaneous chemical modification of aspartyl residues in A\u03b2 to transient succinimide induces a non\u2010native conformation in a fraction of soluble A\u03b2, rendering it amyloidogenic and neurotoxic. Conformationally altered A\u03b2 is characterized by increased stability in solution and the presence of a nonnative \u03b2\u2010turn that determines folding of A\u03b2 in solution and the structure of A\u03b2 subunits incorporated into amyloid fibrils. While the soluble \u2018non\u2010native\u2019 A\u03b2 is both the factor triggering the neurodegenerative cascade and the precursor of amyloid plaques, these two events result from interaction of A\u03b2 with different sets of cellular components and need not coincide in space and time. Extensive literature data and experimental evidence are provided in support of this hypothesis.\u2014Orpiszewski, J., Schormann, N., Kluve\u2010Beckerman, B., Liepnieks, J. J., Benson, M. D. Protein aging hypothesis of Alzheimer disease.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 14, 1255\u20131263 (2000)\n                  <\/jats:p>","DOI":"10.1096\/fasebj.14.9.1255","type":"journal-article","created":{"date-parts":[[2018,1,18]],"date-time":"2018-01-18T07:59:22Z","timestamp":1516262362000},"page":"1255-1263","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Protein aging hypothesis of Alzheimer disease"],"prefix":"10.1096","volume":"14","author":[{"given":"Jozef","family":"Orpiszewski","sequence":"first","affiliation":[{"name":"Aprot Corporation  Carmel Indiana 46082\u20133813 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Schormann","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Indiana University School of Medicine  Indianapolis Indiana 46202 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Kluve-Beckerman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Indiana University School of Medicine  Indianapolis Indiana 46202 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juris J.","family":"Liepnieks","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Indiana University School of Medicine  Indianapolis Indiana 46202 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merrill D.","family":"Benson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Indiana University School of Medicine  Indianapolis Indiana 46202 USA"},{"name":"Richard L. 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