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

TLDR

ApoE alleles influence Alzheimer’s disease risk, with the ɛ4 allele conferring higher risk than ɛ3, and apoE is thought to promote amyloid‑β deposition and its conversion to fibrillar forms. The study aimed to determine how apoE affects amyloid‑β deposition and Alzheimer’s pathology. Researchers compared APP V717F transgenic mice expressing mouse, human, or no apoE (apoE −/−) to assess these effects. Mice expressing mouse or human apoE developed severe plaque‑associated neuritic dystrophy, while apoE‑deficient mice showed minimal degeneration despite amyloid deposition; expression of apoE3 or apoE4 produced fibrillar amyloid deposits and neuritic plaques by 15 months, with apoE4 mice exhibiting more than tenfold greater fibrillar burden, highlighting an isoform‑specific role of apoE in neuritic plaque formation.

Abstract

Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (ɛ4 > ɛ3) 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 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 Aβ 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 Aβ deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP V717F TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.