Soluble apoE/Aβ complex: Mechanism and therapeutic target for APOE4-induced AD risk

Leon M. Tai; Shipra Mehra; Varsha Shete; Steve Estus; G. William Rebeck; Guojun Bu; Mary Jo Ladu

doi:10.1186/1750-1326-9-2

Soluble apoE/Aβ complex: Mechanism and therapeutic target for APOE4-induced AD risk

Leon M. Tai, Shipra Mehra, Varsha Shete, Steve Estus, G. William Rebeck, Guojun Bu, Mary Jo Ladu

Research output: Contribution to journal › Review article › peer-review

105 Scopus citations

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.

Original language	English
Article number	2
Journal	Molecular Neurodegeneration
Volume	9
Issue number	1
DOIs	https://doi.org/10.1186/1750-1326-9-2
State	Published - Jan 4 2014

Bibliographical note

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.

Funding

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.

Funders	Funder number
Alzheimer's Association
National Institute on Aging
National Institutes of Health (NIH)
National Institutes of Health (NIH)
National Institute on Aging	ZEN-08-899000, P01AG030128, R01AG046205
Alzheimer's Drug Discovery Foundation
Center for Clinical and Translational Science, University of Illinois at Chicago	UL1RR029879

Keywords

Alzheimer's disease
Amyloid beta
Apolipoprotein E
Apolipoprotein E/amyloid beta complex
Lipidation
Lipoprotein
Oligomeric amyloid beta

ASJC Scopus subject areas

Molecular Biology
Clinical Neurology
Cellular and Molecular Neuroscience

Access to Document

10.1186/1750-1326-9-2

Cite this

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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.",

keywords = "Alzheimer's disease, Amyloid beta, Apolipoprotein E, Apolipoprotein E/amyloid beta complex, Lipidation, Lipoprotein, Oligomeric amyloid beta",

author = "Tai, \{Leon M.\} and Shipra Mehra and Varsha Shete and Steve Estus and Rebeck, \{G. William\} and Guojun Bu and Ladu, \{Mary Jo\}",

note = "Funding Information: This work was supported, in whole or in part, by NIH/NIA P01AG030128, Alzheimer{\textquoteright}s Association Grant ZEN-08-899000, University of Illinois at Chicago Center for Clinical and Translational Science Grant UL1RR029879 and Alzheimer{\textquoteright}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.",

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doi = "10.1186/1750-1326-9-2",

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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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Soluble apoE/Aβ complex: Mechanism and therapeutic target for APOE4-induced AD risk

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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