Apolipoprotein E isoforms in Alzheimer's disease pathology and etiology.
The apolipoprotein E (apoE) epsilon4 allele increases risk of Alzheimer's disease (AD), perhaps by accelerating plaque formation, or by impairing neuron repair. Considerable evidence supports both mechanisms. AD patients with epsilon4 have more and earlier amyloid deposits than do patients without epsilon4. The same is true of non-demented control subjects. In vitro, all apoE isoforms inhibit amyloid beta protein (Abeta) aggregation, but apoE4 less effectively than apoE3. Transgenic amyloid-producing mice expressing apoE3 or apoE4 develop less Abeta deposition than apoE knockout mice. These observations are consistent with an effect of apoE isoforms on Abeta aggregation in AD. ApoE is important for neurite maintenance since apoE knockout mice lose neurites and suffer behavioral deficits with aging or treatment with excitotoxins. ApoE4 mice show similar defects, but apoE3 mice are normal. AD patients with epsilon4 show more neuritic deficits than epsilon3 carriers. ApoE epsilon4 also worsens neurological impairment in head injury, stroke, and multiple sclerosis. Thus, apoE4 is less effective at neurite maintenance. Perhaps epsilon4 increases AD risk by both mechanisms: allowing amyloid deposition and failing to repair neurites. In either case, introducing apoE3 or apoE2 into the brain, for example by gene therapy or cell grafts, might delay AD progression.
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong. lwbaum@hotmail.com
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D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D020033:Protein Isoforms