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J Mol Neurosci. 2004;23(3):167-79.

ApoE-dependent plasticity in Alzheimer's disease.

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  • 1University of California Los Angeles 90095 and Veteran's Administration-Greater Los Angeles Healthcare System (VA-GLAHS), Sepulveda, CA 91343, USA. bteter@UCLA.edu

Abstract

The contribution of neuroplasticity to Alzheimer's disease (AD) is supported by important effects of apoE on both the pathology of AD and the environmental and developmental factors influencing its etiologies. The earlier age of onset of apoE4 AD patients could be caused by defects in apoE-related compensatory repair mechanisms. The role of apoE in stimulating neuronal regeneration like neurite sprouting has received much support, with apoE4 consistently showing defects both in vitro and in vivo and in AD. In addition, growing evidence indicates that the reduced sprouting activity of apoE4 represents a gain-of-negative function; that is, apoE3-stimulated sprouting increases with increasing apoE3 dose, while any neurite sprouting with apoE4 is decreased with increasing apoE4 dose. Clearly, the dose responses for all relevant apoE activities need evaluation, as well as determination of the physiologically relevant doses in the brain. Because apoE4 plays a major role in the risk and onset of AD for approximately 50% of AD cases, therapies that target the mechanism of this increased risk would greatly impact AD prevalence. Possible targets include apoE expression levels and regulation, and apoE protein structure or gene replacement. The gain-of-negative function of apoE4 in neurite sprouting, or any apoE4-specific activity, could have important clinical implications for the pharmacogenetic efficacy of therapeutic drugs that impact or target apoE expression or activity. Some therapeutic drugs, including estrogen that can regulate apoE levels, show apoE isotype-dependent efficacy in AD therapy. Other candidate drugs that could modulate apoE expression include antioxidants, anti-inflammatories, and statins. The contribution of apoE4 to drug efficacy may distinguish mechanisms of disease onset from those of progression, since the pleiotropic effects of apoE and its isotypes raise the strong possibility that the isotypes differ in the mechanism by which they contribute to AD etiology.

PMID:
15181245
DOI:
10.1385/JMN:23:3:167
[PubMed - indexed for MEDLINE]
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