title: Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk.
abstract: The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) compared to APOE2 and APOE3. Amyloid-β (Aβ), particularly in a soluble oligomeric form (oAβ), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAβ are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAβ levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aβ, namely apoE/Aβ complex, modulate Aβ levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Aβ complexes, resulting in reduced apoE4/Aβ levels and increased accumulation, particularly of oAβ. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed.
authors.forename: Leon M
authors.initials: LM
authors.lastname: Tai
authors.forename: Shipra
authors.initials: S
authors.lastname: Mehra
authors.forename: Varsha
authors.initials: V
authors.lastname: Shete
authors.forename: Steve
authors.initials: S
authors.lastname: Estus
authors.forename: G William
authors.initials: GW
authors.lastname: Rebeck
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S, Wood St,, M/C 512, Chicago, IL 60612, USA. mladu@uic.edu.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: LaDu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D011485:Protein Binding; D012307:Risk Factors; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4