Brain apolipoprotein E levels in mice challenged by a Western diet increase in an allele-dependent manner.

Human apolipoprotein E (APOE) is the greatest determinant of genetic risk for memory deficits and Alzheimer's disease (AD). While APOE4 drives memory loss and high AD risk, APOE2 leads to healthy brain aging and reduced AD risk compared to the common APOE3 variant. We examined brain APOE protein levels in humanized mice homozygous for these alleles and found baseline levels to be age- and isoform-dependent: APOE2 levels were greater than APOE3, which were greater than APOE4. Despite the understanding that APOE lipoparticles do not traverse the blood-brain barrier, we show that brain APOE levels are responsive to dietary fat intake. Challenging mice for 6 months on a Western diet high in fat and cholesterol increased APOE protein levels in an allele-dependent fashion with a much greater increase within blood plasma than within the brain. In the brain, APOE2 levels responded most to the Western diet challenge, increasing by 20 % to 30 %. While increased lipoparticles are generally deleterious in the periphery, we propose that higher brain APOE2 levels may represent a readily available pool of beneficial lipid particles for neurons.

Expression and proteolytic processing of the amyloid precursor protein is unaffected by the expression of the three human apolipoprotein E alleles in the brains of mice.

The 3 human apolipoprotein E (APOE) gene alleles modify an individual's risk of developing Alzheimer's disease (AD): compared to the risk-neutral APOE ε3 allele, the ε4 allele (APOE4) is strongly associated with increased AD risk while the ε2 allele is protective. Multiple mechanisms have been shown to link APOE4 expression and AD risk, including the possibility that APOE4 increases the expression of the amyloid precursor protein (APP) (Y-W.A. Huang, B. Zhou, A.M. Nabet, M. Wernig, T.C. Südhof, 2019). In this study, we investigated the impact of APOE genotype on the expression, and proteolytic processing of endogenously expressed APP in the brains of mice humanized for the 3 APOE alleles. In contrast to prior studies using neuronal cultures, we found in the brain that both App gene expression, and the levels of APP holoprotein were not affected by APOE genotype. Additionally, our analysis of APP fragments showed that APOE genotype does not impact APP processing in the brain: the levels of both α- and ß-cleaved soluble APP fragments (sAPPs) were similar across genotypes, as were the levels of the membrane-associated α- and ß-cleaved C-terminal fragments (CTFs) of APP. Lastly, APOE genotype did not impact the level of soluble amyloid beta (Aß). These findings argue that the APOE-allele-dependent AD risk is independent of the brain expression and processing of APP.