title: Deciphering the mechanism underlying late-onset Alzheimer disease.
abstract: Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
authors.forename: Dimitrije
authors.initials: D
authors.lastname: Krstic
authors.forename: Irene
authors.initials: I
authors.lastname: Knuesel
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D051379:Mice; D016501:Neurites / Q000473:pathology / Q000502:physiology; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology / Q000502:physiology; D057165:Proteostasis Deficiencies / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; C054369:MAPT protein, human; D016875:tau Proteins