Deciphering the mechanism underlying late-onset Alzheimer disease

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Nature Reviews Neurology (Impact Factor: 15.36). 11/2012; 9(1). DOI: 10.1038/nrneurol.2012.236
Source: PubMed


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.

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    • "Supportive of this model, APP expression in the brain of DS is significantly higher than predicted by the gene triplication suggesting that other factors could turn on this gene expression. Cytokines and LPS are candidates as they were found to consistently stimulate amyloid synthesis and induce cognitive impairment [7]. Our own studies showed that in NL subjects, measures of history of PerioD associated with amyloid accumulation in the brain [58] and affect tau protein hyperphos- phorylation [36]. "
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    • "At present, plenty of new data from biomedical research reveals the need to revise current ideas about AD origins. It has been proposed that primary pathological changes, preceding A␤ overproduction and tau pathology, appear in neurons in response to the first hit of damaging factors (reviewed in [13] [14] [15] [16] [17] [18]). Such early pathological changes in AD include calcium dyshomeostasis , mitochondria impairment, an increase in the oxidative stress level, and abnormalities in cell cycle regulation. "
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