Journal of Alzheimer's disease : JADMay 29, 2012

Human apolipoprotein E2 increases brain amyloid buildup and nerve cell loss in mice with blood vessel–linked amyloid protein mutation

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Updated Apr 3, 2026

Abstract

Human ApoE2 does not beneficially influence the accumulation of amyloid pathology in transgenic mice compared to human ApoE4.

APOE genotype impacts the development of Alzheimer's disease and cerebral amyloid angiopathy.
The ε4 allele is associated with increased risk, while the ε2 allele is linked to decreased risk for these conditions.
No significant differences in total levels of Aβ(40) and Aβ(42) were observed between Tg-SwDI mice on human APOE2/2 or APOE4/4 backgrounds and those on a mouse APOE background.
Both human APOE backgrounds resulted in a strong reduction of microvascular cerebral amyloid angiopathy and an increase in parenchymal plaque amyloid.
The distribution of ApoE proteins and neuronal loss were linked to the presence of parenchymal amyloid plaques in both genotypes.
Findings indicate that human ApoE2 does not alter the spatial or quantitative accumulation of mutant amyloid associated with CAA.

Simplified

Human apolipoprotein (ApoE) genotype influences the development of Alzheimer's disease and cerebral amyloid angiopathy (CAA), where the ε4 allele increases and the ε2 allele decreases the risk for developing disease. Specific mutations within the amyloid-β (Aβ) peptide have been identified that cause familial forms of CAA. However, the influence of APOE genotype on accumulation of CAA mutant Aβ in brain is not well understood. Earlier, we showed that human ApoE4 redistributes fibrillar amyloid deposition from the cerebral microvasculature to parenchymal plaques in Tg-SwDI mice, a model that accumulates human Dutch/Iowa (E22Q/D23N) CAA mutant Aβ in brain (Xu et al., J Neurosci 28, 5312-5320, 2008). Human ApoE2 can reduce Aβ pathology in transgenic models of parenchymal plaques. Here we determined if human ApoE2 can influence the location and severity of amyloid pathology in Tg-SwDI mice. Comparing Tg-SwDI mice bred onto a human APOE2/2 or human APOE4/4 background, we found there was no change in the brain levels of total Aβ(40) and Aβ(42) compared to mice on the endogenous mouse APOE background. In Tg-SwDI mice on either human APOE background, there was a similarly strong reduction in the levels of microvascular CAA and emergence of extensive parenchymal plaque amyloid. In both Tg-SwDI-hAPOE2/2 and Tg-SwDI-hAPOE4/4 mice, the distribution of ApoE proteins and neuronal loss were associated with parenchymal amyloid plaques. These findings suggest that compared with human ApoE4, human ApoE2 does not beneficially influence the quantitative or spatial accumulation of human Dutch/Iowa CAA mutant amyloid or associated pathology in transgenic mice.

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Human apolipoprotein E2 increases brain amyloid buildup and nerve cell loss in mice with blood vessel–linked amyloid protein mutation

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