Alteration of the Endocannabinoid System in Human Alzheimer’s Disease Brain

There is a growing interest in the endocannabinoid (EC) system, which includes the cannabinoid receptors 1 & 2 (CB1R & CB2R) and the enzymes that degrade/regulate endogenous ligands. These enzymes include Fatty Acid Amide Hydrolase (FAAH), which degrades anandamide, a ligand for the CB1R, and Monoacylglycerol Lipase (MAGL), which degrades 2-arachidonoylglycerol, a ligand for the CB2R. Yet the roles of the CBR and enzymes in Alzheimer's Disease (AD) remain inconclusive and controversial. Therefore, our project objective was to investigate changes, if any, in endocannabinoid signalling within human Alzheimer's disease brains. We hypothesized (1) FAAH expression would correlate with a decrease in CB1R expression in AD brains (2). Furthermore, we expected sex-dependent differences as such differences have been shown in the EC in brains. Two EC proteins were analyzed in three different brain areas in 60 AD brain samples. Western blots were assayed, and densitometry was performed to quantify the bands of interest using the LI-COR software. Our research demonstrated that the EC is indeed altered in AD brains, with CB1R expression increasing in the hippocampus. Furthermore, we found a sex-dependent difference in the EC alteration, with females having a greater expression of CB1R in the hippocampus compared to males. Finally, a strong correlation was observed between CB1R expression and FAAH expression in the cortex, hippocampus, and cerebellum of males, but no such correlation existed in the female data. Therefore, we refuted our first hypothesis but accepted the second one. Our data suggests that CB1R expression is regulated by FAAH activity in males but not females. Our research provides evidence of the possibility that AD follows distinct progressions in males and females with the same pathophysiological late-stage symptoms.