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ApoE and Aβ1–42 interactions

Effects of isoform and conformation on structure and function

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Abstract

Abnormalities in the processing of amyloid precursor protein to amyloid-β (Aβ) are causal factors, and the presence of the ε4 allele of apolipoprotein E (apoE) is the primary risk factor for Alzheimer’s disease (AD). Based, at least in part, on these genetics, the potential structural and functional interactions between these two proteins are the focus of our research. To understand the nature of the physical interactions between apoE and Aβ, we initially utilized gel-shift assays to demonstrate that native apoE2 and E3 (associated with lipid particles) form an SDS-stable complex with Aβ that is more abundant than the apoE4:Aβ complex. We further demonstrated that exogenous apoE3 but not E4 prevents Aβ-induced neurotoxicity by a process that requires apoE receptors. In addition, both exogenous apoE3 and E4 prevent Aβ-induced, glial-mediated inflammation, also via a process that requires apoE receptors. These functional effects all occur at a molar ratio of apoE to Aβ of 1:30. Because the biological activities for both apoE and Aβ are profoundly influenced by their isoform and conformation, respectively, we further investigated the idea that apoE3 and E4 differentially interact with particular aggregation species of Aβ1–42. Our overall hypothesis is that apoE has two general functions in relation to Aβ. First, apoE interacts with oligomeric Aβ via an apoE receptor-mediated process to inhibit neurotoxicity and neuroinflammation (apoE3>apoE4) a process possibly related to binding and clearance of apoE3:oligomer complexes. Second, apoE facilitates the deposition of Aβ as amyloid (apoE4 \s>apoE3). We will continue to investigate the effect of apoE isoform and Aβ conformation on the structural and functional interactions between these two proteins in relation to the pathogenesis of AD.

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Authors and Affiliations

  1. Department of Medicine, Division of Geriatrics, Evanston Northwestern Healthcare Research Institute, 60201, Evanston, Illinois

    Arlene M. Manelli, W. Blaine Stine & Mary Jo LaDu

  2. Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 60611, Chicago, IL

    Linda J. Van Eldik

  3. Department of Drug Discovery Program, Feinberg School of Medicine, Northwestern University, 60611, Chicago, IL

    Linda J. Van Eldik & Mary Jo LaDu

  4. Department of Alzheimer’s Disease Core Center, Feinberg School of Medicine, Northwestern University, 60611, Chicago, IL

    Linda J. Van Eldik & Mary Jo LaDu

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  1. Arlene M. Manelli
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  2. W. Blaine Stine
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  4. Mary Jo LaDu
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Correspondence to Mary Jo LaDu.

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Manelli, A.M., Stine, W.B., Van Eldik, L.J. et al. ApoE and Aβ1–42 interactions. J Mol Neurosci 23, 235–246 (2004). https://doi.org/10.1385/JMN:23:3:235

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