| First Author | Youmans KL | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 50 | Pages | 41774-86 |
| PubMed ID | 23060451 | Mgi Jnum | J:193422 |
| Mgi Id | MGI:5468392 | Doi | 10.1074/jbc.M112.407957 |
| Citation | Youmans KL, et al. (2012) APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem 287(50):41774-86 |
| abstractText | APOE4 is the greatest risk factor for Alzheimer disease (AD) and synergistic effects with amyloid-beta peptide (Abeta) suggest interactions among apoE isoforms and different forms of Abeta accumulation. However, it remains unclear how the APOE genotype affects plaque morphology, intraneuronal Abeta, soluble Abeta42, and oligomeric Abeta (oAbeta), 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, Abeta deposition was delayed by approximately 4 months in the EFAD mice, allowing detection of early changes in Abeta 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 Abeta accumulation in EFAD mice. In E4FAD mice, total apoE levels were lower and total Abeta 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 Abeta42 and oAbeta levels were highest in E4FAD mice, although soluble apoE2, apoE3, and apoE4 levels were comparable, suggesting that the differences in soluble Abeta42 and oAbeta result from functional differences among the apoE isoforms. Thus, APOE differentially regulates multiple aspects of Abeta accumulation. |
