Grant: China-Canada Joint Health Research Initiative

AD is characterized by accumulation and deposition of pathogenic Abeta peptides in the brain. Family AD results from inherited mutations in genes involving Abeta peptide production. The majority of Alzheimer's patients are sporadic late-onset cases (LOAD). The pathogenic mechanisms of LOAD are still elusive. A number of epidemic and genetic studies including genome-wide association studies (GWAS) suggested that altered cholesterol metabolism is linked to LOAD pathogenesis. Experimental studies have shown that increased levels of cellular cholesterol promotes the production and deposition of Abeta peptides in the brain. ApoE proteins (ApoE2, 3, and 4) are the main cholesterol transport proteins in the brain. ApoE4 which is not efficient in cholesterol transport is a recognized risk factor of LOAD. Changes in genes (such as single nucleotide polymorphisms -SNP) involving cholesterol/lipid metabolism may predispose the carriers to the development of LOAD. Our previous study has demonstrated that cholesterol retention occurs in LOAD brain with increased beta-and gamma secretase activities and increased ABeta production. We have also identified nine nuclear receptors (transcription factors) involving cholesterol/lipid metabolism from LOAD brain. The levels and activities of these nuclear receptors are altered in LOAD brain as compared to age-matched non-demented controls (ND). This collaborative study is aimed to identify the SNPs in these nuclear receptor genes in LOAD vs. ND humans and to characterize the effects of the identified genetic changes on the expression of the nuclear receptors, cholesterol/lipid metabolism, secretase activities and Abeta processing/production using in vitro cell model systems. This will validate whether genetic changes in these nuclear receptor genes that regulate cholesterol metabolism are responsible for altered cholesterol metabolism in the brain and are involved in LOAD pathogenesis.