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Deciphering the mechanism underlying late-onset Alzheimer disease.

  • Krstic D Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
  • Knuesel I
  • 2012-11-28
Published in:
  • Nature reviews. Neurology. - 2013
Aged
Alzheimer Disease
Amyloid beta-Peptides
Animals
Brain
Cell Death
Disease Models, Animal
Disease Progression
Humans
Inflammation Mediators
Mice
Neurites
Neurofibrillary Tangles
Proteostasis Deficiencies
tau Proteins
English 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.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/287088
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