title: Impact of apolipoprotein E on Alzheimer's disease.
abstract: A key feature of Alzheimer's disease (AD) is deposition of extracellular amyloid plaque comprised chiefly of the amyloid β (Aβ) peptide. Studies of Aβ have shown that it may be catabolized by proteolysis or cleared from brain via members of the low-density lipoprotein receptor family. Alternatively, Aβ can undergo a conformational transition from α-helix to β-sheet, a conformer that displays a propensity to self-associate, oligomerize and form fibrils. Furthermore, β- sheet conformers catalyze conversion of other α-helical Aβ peptides to β-sheet, feeding the oligomer and fibril assembly process. A factor that influences the fate of Aβ in the extracellular space is apolipoprotein (apo) E. Polymorphism at position 112 or 158 in apoE give rise to three major isoforms. One isoform in particular, apoE4 (Arg at 112 and 158), has generated considerable interest since the discovery that it is the major genetic risk factor for development of late onset AD. Despite this striking correlation, the molecular mechanism underlying apoE4's association with AD remains unclear. A tertiary structural feature distinguishing apoE4 from apoE2 and apoE3, termed domain interaction, is postulated to affect the conformation and orientation of its' two independently folded domains. This feature has the potential to influence apoE4's interaction with Aβ, its sensitivity to proteolysis or its lipid accrual and receptor binding activities. Thus, domain interaction may constitute the principal molecular feature of apoE4 that predisposes carriers to late onset AD. By understanding the contribution of apoE4 to AD at the molecular level new therapeutic or prevention strategies will emerge.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609 USA. rryan@chori.org.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Hauser
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ryan
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D012307:Risk Factors
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E
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