TY - JOUR
T1 - Soluble apoE/Aβ complex
T2 - Mechanism and therapeutic target for APOE4-induced AD risk
AU - Tai, Leon M.
AU - Mehra, Shipra
AU - Shete, Varsha
AU - Estus, Steve
AU - Rebeck, G. William
AU - Bu, Guojun
AU - Ladu, Mary Jo
N1 - Funding Information:
This work was supported, in whole or in part, by NIH/NIA P01AG030128, Alzheimer’s Association Grant ZEN-08-899000, University of Illinois at Chicago Center for Clinical and Translational Science Grant UL1RR029879 and Alzheimer’s Drug Discovery Foundation Grant to MJL. MJL would like to acknowledge Skip Binder for his 20+ years of contributions to her study of Aβ, albeit “an irrelevant peptide”. His opinions will be sorely missed.
PY - 2014/1/4
Y1 - 2014/1/4
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Amyloid beta
KW - Apolipoprotein E
KW - Apolipoprotein E/amyloid beta complex
KW - Lipidation
KW - Lipoprotein
KW - Oligomeric amyloid beta
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UR - http://www.scopus.com/inward/citedby.url?scp=84891502796&partnerID=8YFLogxK
U2 - 10.1186/1750-1326-9-2
DO - 10.1186/1750-1326-9-2
M3 - Review article
C2 - 24386905
AN - SCOPUS:84891502796
SN - 1750-1326
VL - 9
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 2
ER -