Journal
NATURE REVIEWS NEUROLOGY
Volume 9, Issue 1, Pages 25-34Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nrneurol.2012.236
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Funding
- Swiss National Science Foundation [310030-132629]
- Gottfried und Julia Bangerter-Rhyner Foundation
- Olga Mayenfisch Foundation
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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-beta (A beta) 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 Aa and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A beta accumulation in late-onset AD. Krstic, D. & Knuesel, I. Nat. Rev. Neurol. 9, 25-34 (2013); published online 27 November 2012; doi:10.1038/nrneurol.2012.236
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