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 journalReview articlepeer-review

93 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 languageEnglish
Article number2
JournalMolecular Neurodegeneration
Volume9
Issue number1
DOIs
StatePublished - 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.

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

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