LDLR Genetics, Splicing and AD Risk

Identifying genetic variants that significantly alter the function of proteins critical to the human organism provides insights into related disease processes and possible therapies. Here, we have identified low density lipoprotein receptor (LDLR) haplotypes that are associated with quantitative differences in splicing of LDLR exons 11 and 12; this alternative splicing is predicted to generate a soluble form of the receptor that acts as a dominant negative form of the protein. This proposal focuses on identifying the specific SNPs that modulate LDLR splicing, elucidating the function of the soluble LDLR isoforms, and evaluating whether the splicemodulating SNPs are detected as risk factors for altered cholesterol homeostasis as well as a disease that may be modulated by cholesterol homeostasis, i.e., Alzheimers disease. The foundation for this proposal is preliminary studies wherein we have generated preliminary data supporting each of the Specific Aims, which include 1. Identify LDLR SNPs and haplotypes that alter LDLR splicing and lor expression, 2. Evaluate the expression and function of soluble LDLR proteins resulting from alternative LDLR splicing, 3. Evaluate LDLR genotypes and haplotypes for their association with (a) cholesterol homeostasis, (b) AD risk, and (c) haHmarks of AD pathology, and 4. Evaluate the role of LDLR deficiency and ectopic expression of variant LDLR on cholesterol homeostasis and An clearance in vivo. Hence, this proposed approach will directly evaluate the hypothesis that LDLR polymorphisms modulate LDLR splicing and function to increase LDL-cholesterol and AD odds. Overall, these studies are significant in that identifying LDLR SNPs that alter LDLR function will be relevant to diseases involving altered cholesterol homeostasis, which likely includes AD and certainly includes diseases in addition to AD, e.g., cardiovascular disease.