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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    • "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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    • "Thus, it is possible that these hallmarks of AD pathology originate from chronic systemic inflammation— as a function of aging combined with proinflammatory genetic and lifestyle factors (for review see Watt, 2014)—but then serve to exacerbate neuroinflammation and thereby accelerate AD onset and progression. As such, accumulation and/or the clearance failure of Aβ plaques and NFTs may be more related to chronic inflammation than previously recognized (Krstic and Knuesel, 2013; François et al., 2014). Indeed, evidence is growing in support of a neuroinflammatory perspective of AD—which acknowledges amyloid as a critical component in the disease process—but sees much of the damage in AD to be better associated with the effects of chronic inflammation (for review see Akiyama et al., 2000). "
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    • "Although the central nervous system has classically been considered a site of immune privilege, recent studies have shown that immune cells can infiltrate the brain under certain pathologic conditions (Friese et al., 2004; Lucin and Wyss-Coray, 2009). The major causative factor of Alzheimer's disease (AD), beta-amyloid (Ab), has been shown to be associated with brain inflammatory responses and to activate microglia and monocytes (Fiala et al., 2007; Hickman and El Khoury, 2013; Krstic and Knuesel, 2013), raising the possibility that immune responses might play a role in the pathophysiology of AD. However, it is unknown whether and how innate immune cells are involved in the progress of AD (Fortin et al., 2008). "
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