Reducing Human Apolipoprotein E Levels Attenuates Age-Dependent Aβ Accumulation in Mutant Human Amyloid Precursor Protein Transgenic Mice

Apolipoprotein E4 (apoE4) plays a major role in the pathogenesis of Alzheimer's disease. Brain amyloid-beta (A beta) accumulation depends on age and apoE isoforms (apoE4 > apoE3) both in humans and in transgenic mouse models. Brain apoE levels are also isoform dependent, but in the opposite direction (apoE4 < apoE3). Thus, one prevailing hypothesis is to increase brain apoE expression to reduce A beta levels. To test this hypothesis, we generated mutant human amyloid precursor protein transgenic mice expressing one or two copies of the human APOE3 or APOE4 gene that was knocked in and flanked by LoxP sites. We report that reducing apoE3 or apoE4 expression by 50% in 6-month-old mice results in efficient A beta clearance and does not increase A beta accumulation. However, 12-month-old mice with one copy of the human APOE gene had significantly reduced A beta levels and plaque loads compared with mice with two copies, regardless of which human apoE isoform was expressed, suggesting a gene dose-dependent effect of apoE on A beta accumulation in aged mice. Additionally, 12-month-old mice expressing one or two copies of the human APOE4 gene had significantly higher levels of A beta accumulation and plaque loads than age-matched mice expressing one or two copies of the human APOE3 gene, suggesting an isoform-dependent effect of apoE on A beta accumulation in aged mice. Moreover, Cre-mediated APOE4 gene excision in hippocampal astrocytes significantly reduced insoluble A beta in adult mice. Thus, reducing, rather than increasing, apoE expression is an attractive approach to lowering brain A beta levels.