APOE4-specific Changes in A beta Accumulation in a New Transgenic Mouse Model of Alzheimer Disease
journal contributionposted on 06.12.2013, 00:00 by Katherine L. Youmans, Leon M. Tai, Evelyn Nwabuisi-Heath, Lisa Jungbauer, Takahisa Kanekiyo, Ming Gan, Jungsu Kim, William A. Eimer, Steve Estus, G. William Rebeck, Edwin J Weeber, Guojun Bu, Chunjiang Yu, Mary Jo LaDu
APOE4 is the greatest risk factor for Alzheimer disease (AD) and synergistic effects with amyloid-beta peptide (A beta) suggest interactions among apoE isoforms and different forms of A beta accumulation. However, it remains unclear how the APOE genotype affects plaque morphology, intraneuronal A beta, soluble A beta 42, and oligomeric A beta (oA beta), particularly in vivo. As the introduction of human APOE significantly delays amyloid deposition in transgenic mice expressing familial AD (FAD) mutations (FAD-Tg), 5xFAD-Tg mice, which exhibit amyloid deposition by age 2 months, were crossed with apoE-targeted replacement mice to produce the new EFAD-Tg mice. Compared with 5xFAD mice, A beta deposition was delayed by similar to 4 months in the EFAD mice, allowing detection of early changes in A beta accumulation from 2-6 months. Although plaque deposition is generally greater in E4FAD mice, E2/E3FAD mice have significantly more diffuse and E4FAD more compact plaques. As a first report in FAD-Tg mice, the APOE genotypes had no effect on intraneuronal A beta accumulation in EFAD mice. In E4FAD mice, total apoE levels were lower and total A beta levels higher than in E2FAD and E3FAD mice. Profiles from sequential three-step extractions (TBS, detergent, and formic acid) demonstrated that the lower level of total apoE4 is reflected only in the detergent-soluble fraction, indicating that less apoE4 is lipoprotein-associated, and perhaps less lipidated, compared with apoE2 and apoE3. Soluble A beta 42 and oA beta levels were highest in E4FAD mice, although soluble apoE2, apoE3, and apoE4 levels were comparable, suggesting that the differences in soluble A beta 42 and oA beta result from functional differences among the apoE isoforms. Thus, APOE differentially regulates multiple aspects of A beta accumulation.