APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease

Oct 13, 2012The Journal of biological chemistry

APOE4-related changes in amyloid beta buildup in a new Alzheimer’s mouse model

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Abstract

Aβ deposition was delayed by ∼4 months in EFAD mice compared to 5xFAD mice.

APOE genotypes influenced plaque morphology, with E2/E3FAD mice showing more diffuse plaques and E4FAD mice exhibiting more compact plaques.
No difference in intraneuronal Aβ accumulation was observed among different APOE genotypes in EFAD mice.
E4FAD mice had lower total apoE levels and higher total Aβ levels compared to E2FAD and E3FAD mice.
Lower levels of apoE4 were primarily found in the detergent-soluble fraction, indicating less lipoprotein association compared to apoE2 and apoE3.
Soluble Aβ42 and oligomeric Aβ levels were highest in E4FAD mice, potentially reflecting functional differences among apoE isoforms.

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APOE4 is the greatest risk factor for Alzheimer disease (AD) and synergistic effects with amyloid-β peptide (Aβ) suggest interactions among apoE isoforms and different forms of Aβ accumulation. However, it remains unclear how the APOE genotype affects plaque morphology, intraneuronal Aβ, soluble Aβ42, and oligomeric Aβ (oAβ), 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, Aβ deposition was delayed by ∼4 months in the EFAD mice, allowing detection of early changes in Aβ 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 Aβ accumulation in EFAD mice. In E4FAD mice, total apoE levels were lower and total Aβ 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 Aβ42 and oAβ levels were highest in E4FAD mice, although soluble apoE2, apoE3, and apoE4 levels were comparable, suggesting that the differences in soluble Aβ42 and oAβ result from functional differences among the apoE isoforms. Thus, APOE differentially regulates multiple aspects of Aβ accumulation.

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APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease

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