Abstract
The cholesteryl ester transfer protein (CETP) is a lipid transfer protein responsible for the exchange of cholesteryl esters and triglycerides between lipoproteins. Decreased CETP activity is associated with longevity, cardiovascular health, and maintenance of good cognitive performance. Interestingly, mice lack the CETP-encoding gene and have very low levels of low-density lipoprotein (LDL) particles compared to humans. To understand how CETP activity affects the brain, we utilised CETP transgenic (CETPtg) mice showing elevated LDL levels on a high cholesterol diet inducing CETP expression. We found that CETPtg mice had up to 25% higher cholesterol levels in the brain. Using a microarray on astrocyte-derived mRNA, we found that this cholesterol increase is likely not due to astrocytic-dependent de novo synthesis of cholesterol. Rather, several genes linked to Alzheimer’s disease were altered in CETPtg mice. Most interestingly, we found activation of the G-protein coupled receptor EP4 and γ-secretase as upstream regulators of these transcriptional changes. Further in vitro studies showed that CETP expression was sufficient to activate γ-secretase activity. The data suggest that CETP activity affects brain’s health through modulating cholesterol levels and Alzheimer’s-related pathways. Therefore, CETPtg mice constitute a valuable research tool to investigate the impact of the cholesterol metabolism on brain functions.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding: This work was funded by the Alzheimer Society of Canada Young Investigator grant PT-58872 and regular Research Grant 17-02, the Weston Brain Institute award RR172187, and the Canadian Institute of Health Research CIHR-PJT-162302, and was supported by the Fonds de recherche du Québec - santé FRQS research allocation FRQ-S 36571, the Canada Foundation of Innovation Leaders Opportunity Fund Grant 32565, and Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants RGPIN-2015-04645 to LM and RGPIN-2015-06802 to PC. ARdS acknowledges support from CIHR project grant PJT-166195. FO received studentships through the Integrated Program in Neuroscience (IPN) and from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives initiative. NY was the recipient of a doctoral studentship from the Louise and Alan Edwards Foundation. EY received a doctoral studentship from NSERC.
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE111242