Introduction: Genetic variants within the APOE-TOMM40 locus are associated with Alzheimer's disease (AD). A specific role for TOMM40 is indicated by the finding that '523' poly-T variants are associated with AD risk, but the mechanism for this effect has not been established. Our studies have shown that suppression of Tomm40 in mice increased brain cholesterol content, an AD risk factor, and thus the present study sought to assess whether major '523' poly-T variants (Short [S] and Very Long [VL]) are associated with altered lipid content of brain and other tissues. Methods: We utilized a mouse model containing the entire human APOE3-TOMM40 locus to quantify cholesterol and triglyceride levels in brain, liver, and white adipose tissue (WAT), as well as brain content of the AD biomarkers A{beta} 42 and tau, in mice carrying two homozygous TOMM40 '523' poly-T genotypes (S/S and VL/VL). Results: Male mice carrying the '523'-S/S genotype, but not females, showed higher brain cholesterol and triglyceride levels than VL/VL carriers, together with greater brain A{beta} 42 content. WAT showed similar lipid differences as in the brain, while hepatic lipid content was broadly similar between '523'-S/S and -VL/VL genotypes, though there was a trend for higher triglycerides in VL/VL mice in a sex- and age- dependent manner. Discussion: These results demonstrate that TOMM40 '523' poly-T variants drive tissue-specific, sex-, and age-dependent lipid differences in humanized APOE3-TOMM40 mice, with the S/S genotype linked to elevated brain cholesterol and A{beta} 42 levels, effects that link this locus to AD pathogenesis.
Yang, N. V., Hodgson, D., Jang, T. M., Kim, J. J., Gottschalk, W. K., Yassine, H. N., Chiba-Falek, O., Krauss, R. M.
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