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$(\varepsilon 4>\varepsilon 3)$for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-β (Aβ) peptide and its conversion to a fibrillar form. To determine the effect of apoE on Aβ deposition and AD pathology, we compared APPV717Ftransgenic (TG) mice expressing mouse, human, or no apoE (apoE-/-). A severe, plaque-associated neuritic dystrophy developed in APPV717FTG mice expressing mouse or human apoE. Though significant levels of Aβ deposition also occurred in APPV717FTG, apoE-/-mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APPV717FTG, apoE-/-mice resulted in fibrillar Aβ deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APPV717FTG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.