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 Alzheimers disease were altered in CETPtg mice. Most interestingly, we found activation of the G-protein coupled receptor EP4 and {gamma}-secretase as upstream regulators of these transcriptional changes. Further in vitro studies showed that CETP expression was sufficient to activate {gamma}-secretase activity. The data suggest that CETP activity affects brains health through modulating cholesterol levels and Alzheimers-related pathways. Therefore, CETPtg mice constitute a valuable research tool to investigate the impact of the cholesterol metabolism on brain functions.