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ApoE Remodeling as a Therapeutic Target for Alzheimer's Disease
Author(s) -
Ladu Mary Jo,
AvilaMunoz Maria Evangelina,
ValenciaOlvera Ana,
Ghura Shivesh,
Collins Nicole,
Balu Deebika,
York Jason
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.814.4
Subject(s) - abca1 , apolipoprotein e , lipid anchored protein , neurodegeneration , cholesterol , apolipoprotein b , biology , pharmacology , endocrinology , medicine , transporter , disease , biochemistry , autophagy , apoptosis , gene
APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15‐fold compared to APOE3 . As ɛ4 carriers can respond anomalously in clinical trials, there is a critical lack of therapeutics targeting mechanistic pathways of APOE4 ‐induced AD risk. APOE4 is associated with accelerated amyloid‐β (Aβ) accumulation, both as amyloid and soluble oligomeric forms of Aβ (oAβ), the latter considered a proximal neurotoxin. Using EFAD mice, a new tractable preclinical mouse model (expressing 5 familial AD (FAD) mutations and the human APOE genotypes), we have developed the mechanistic hypothesis that apoE4 is poorly lipidated compared to apoE3, resulting in lower levels of apoE/Aβ complex and higher levels of soluble oAβ. ABCA1 is a promising therapeutic target for testing this hypothesis, as it is a major transporter of lipid to nascent apoE‐containing lipoproteins in the CNS. We previously demonstrated that treatment with RXR agonists increased ABCA1 levels, apoE4 lipidation, and soluble apoE4/Aβ complex levels, while lowering soluble Aβ levels. However, while these data provide target validation for ABCA1, the detrimental effects on the liver limit RXR agonist utility in even short‐term treatment protocols. Therefore, we have identified and are evaluating alternative pharmacological approaches to enhance apoE lipidation, modeling our approach on the peripheral targets for lipoprotein biogenesis and remodeling common in the cardio‐vascular field. Two therapeutic approaches of particular interest are an ABCA1 agonist (Compound A) and an Acyl‐CoA:cholesterol acyltransferase (ACAT) inhibitor (Compound B) to increase cholesterol efflux and free cholesterol availability, respectively. In vitro, both compounds facilitated cholesterol efflux from primary glia and increased the concentration and lipidation of apoE. In vivo, both compounds are brain penetrant and further analysis is on going, including treatment and prevention paradigms with read‐outs that include biochemical and AD pathology, as well as behavioral measurements. Support or Funding Information P01AG044682, R21AG030128, R21AG048498, R21AG051233, CCTS (UL1RR029879)