Diesel exposure and ApoE genotype interact to induce hippocampus‐dependent cognitive behavior deficits in a humanized mouse model: Developing topics. (7th December 2020)

• Record Type: Journal Article
• Authors: Mommer, Brett C; Abel, Glen; Storm, Daniel; Xia, Zhengui
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.047625
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: In humans the ApoE gene, particularly the ApoE4 allele, is the major risk factor for the development of Alzheimer's Disease (AD) dementia. The allele's incomplete penetrance indicates that environmental factors play an important part in disease development and, indeed, environmental exposures such as high doses of heavy metals have been shown to interact with ApoE in animal models, exacerbating AD‐typical cognitive decline. Epidemiological evidence suggests that other exposures, such as industrial and traffic‐related air pollution (TRAP) that human populations are commonly exposed to, is associated with cognitive decline and AD pathology in humans. Recent studies in mice show that exposure to diesel exhaust, a simulation of TRAP exposure, perturbs hippocampal gene expression, inhibits adult hippocampal neurogenesis, and impairs the formation of hippocampus‐dependent memory. Methods: In this study we investigated, in male and female humanized ApoE‐KI mice, whether diesel exposure (DE) at a modest, human‐relevant concentration of particulate matter (PM2.5 under 200ug/m 3 ) was sufficient to induce a deficit in the formation of hippocampus‐dependent short‐term spatial working memory in both the Novel Object Location (NOL) and Cued‐Contextual Fear tests, and whether ApoE genotype altered the timing or severity of the deficit. Results: We found that exposure leads to a deficit in both the hippocampus‐dependent NOL and contextual fear tests but not in the hippocampus‐independent, amygdala‐dependent cued fear test, and the onset and severity of the deficits depended on ApoE genotype. ApoE4 mice developed a DE‐induced deficit earlier than ApoE3 mice. Further, we found that ApoE2 mice experienced a DE‐induced deficit later than ApoE3 mice, supporting a protective role of ApoE2. The gene‐by‐environment interaction (GxE) also depended on sex, with the detrimental effect of ApoE4 most pronounced in males and the protective effect of ApoE2 most pronounced in females. Conclusions: These findings, presented here first, suggest that the prevalence among human populations of widespread particulate matter exposures found to affect laboratory animals' hippocampal function, coupled with human population‐level heterogeneity of ApoE alleles, could underlie a GxE between diesel and ApoE on the development of AD dementia.