| The genetics of Alzheimer's disease (AD) includes causal factors, specifically autosomal dominant mutations that increase the 42 amino acid form of amyloid-beta (Abeta) peptide and apolipoprotein E4 (apoE4), the primary risk factor compared to apoE3, with apoE2 reducing risk. While the toxic form of Abeta remains unclear, soluble and intraneuronal Abeta42 are considered the more proximate cause of neurodegeneration associated with AD. We propose that apoE2 reduces AD risk by preventing or delaying intraneuronal Abeta42 accumulation, while apoE4 increases toxic soluble Abeta42. To test these hypotheses, mice expressing each human apoE isoform (apoE2, E3 and E4-targeted replacement) were crossed with mice that significantly overproduce Abeta42 (5xFAD), generating EFAD mice. The progression of Abeta pathology in EFAD mice develops from 2 to 6 months, initiating as intraneuronal Abeta in the subiculum and deep frontal cortex. Plaque deposition follows intraneuronal Abeta in these AD-susceptible regions, and is absent from the disease-resistant cerebellum. Intraneuronal Abeta is lowest with apoE2 and greatest with apoE4, suggesting that the protective effects of apoE2 may be mediated by a reduction of toxic intraneuronal Abeta. Surprisingly, total plaque burden in 6-month-old mice is equivalent in the presence of apoE2 and apoE4. This apoE2-induced plaque deposition is novel in a mouse model and consistent with work demonstrating that plaque load does not correlate with dementia. Interestingly, apoE2 and apoE3 maintain plaques in a diffuse conformation, while apoE4 facilitates dense-core plaque deposition. Thus, plaque conformation is modulated in an apoE isoform-specific manner. In addition, total apoE4 levels are lower than apoE2 or apoE3, independent of age or brain region, and apoE4 is primarily soluble. Soluble Abeta42 is selectively increased in the presence of apoE4, and this enrichment of Abeta42 and apoE4 in soluble brain fractions provides an opportunity for direct interactions between the toxic form of Abeta and apoE4. The current studies are the first reports of a mouse model in which apoE isoform directly influences intraneuronal Abeta, extracellular plaque morphology, and soluble Abeta42. EFAD mice offer scientists a tractable research tool for critical evaluations of AD biomarkers and the development of therapeutic strategies, with the ultimate goal of preventing AD. |
