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Neurobiol Aging. 2011 Aug;32(8):1341-71. doi: 10.1016/j.neurobiolaging.2009.08.007. Epub 2009 Sep 22.

Alzheimer's disease as homeostatic responses to age-related myelin breakdown.

Author information

  • Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. gbar@ucla.edu

Abstract

The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Aβ deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Aβ and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides "upstream" treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin.

Copyright © 2009 Elsevier Inc. All rights reserved.

PMID:
19775776
[PubMed - indexed for MEDLINE]
PMCID:
PMC3128664
Free PMC Article
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