Cholesterol metabolism in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia and affects around 24 million individuals worldwide. Several studies showed an association between high plasma low-density lipoprotein (LDL) levels and an increased risk of developing AD. To that effect, multiple drugs treating hypercholesterolaemia, such as statins, have been tested to prevent AD. In this study, we propose a new pharmacological target called Cholesteryl Ester Transfer Protein (CETP). In recent years, studies have shown an association between different genetic variants of CETP and the risk of developing AD. CETP is a plasma shuttle protein which promotes the transfer of cholesteryl esters from anti-atherogenic (high-density lipoprotein or HDL) particles to pro-atherogenic (LDL and very-low-density lipoproteins or VLDL) particles. The net effect of this interaction leads to more pro-atherogenic lipoproteins in plasma. Interestingly, CETP is expressed by astrocytes in the brain. Therefore, we propose that CETP inhibition may have general beneficial effects and prevent the development of AD.

METHOD: We assessed the effect of CETP expression and inhibition in cell culture and mouse models. Mice from four different genotypes were used: wildtype (WT), human CETP transgenic mice (hCETP), human APP transgenic mice (McGill-Thy1-hAPP), and hAPP/hCETP double transgenic mice. CETP inhibitor evacetrapib or vehicle were administered i.p. at 2 months of age every day for 10 weeks, followed by cognitive tests and biochemical analyses.

RESULT: CETP expression in cell cultures increased the production of A-beta peptides, whereas CETP inhibition normalized A-beta levels. In mice, we showed that at 5 months of age, female hAPP mice were cognitively impaired both in the evacetrapib and vehicle condition. Double transgenic hAPP/CETP female mice performed worse as compared to hAPP females indicating that CETP aggravated AD. Administration of evacetrapib apparently rescued the cognitive deficits elicited through CETP. Preliminary biochemical results indicate that A-beta levels are increased in double transgenic hAPP/CETP mice as compared to hAPP.

CONCLUSION: CETP may play an aggravating role in AD, which has not yet been investigated since mice naturally lack CETP. We propose that CETP inhibitors such as evacetrapib may be promising pharmacological treatments contributing to the prevention of cognitive decline in AD.