Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease

Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (epsilon 4 > epsilon 3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-beta (A beta) peptide and its conversion to a fibrillar form. To determine the effect of apoE on A beta deposition and AD pathology, we compared App(V717F) transgenic (TG) mice expressing mouse, human, or no apoE (apoE(-/-)). A severe, plaque-associated neuritic dystrophy developed in App(V717F) TG mice expressing mouse or human apoE. Though significant levels of A beta deposition also occurred in App(V717F) TG, apoE(-/-) mice, neuritic degeneration was virtually absent, Expression of apoE3 and apoE4 in App(V717F) TG, apoE(-/-) mice resulted in fibrillar A beta deposits and neuritic plaques by 15 months of age and substantially (> 10-fold) more fibrillar deposits were observed in apoE4-expressing App(V717F) TC mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.