TOMM40 '523' genotype induces sex- and tissue- specific differences in cholesterol and triglyceride levels in an APOE-TOMM40 humanized mouse model

IntroductionGenetic variants within the APOE-TOMM40 locus are associated with Alzheimers 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. MethodsWe 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). ResultsMale 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. DiscussionThese 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.