Molecular Phenotyping of AD Positional Candidate Genes

Drexel University, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the greatest public health problems in the U.S., and its impact will only increase with demographic changes anticipated in the coming decades. Our growing understanding of AD genetics has been central to the explosion in knowledge of AD biology. Recent studies suggest that most of the genetic risk factors for Alzheimer's disease remain allusive. Efforts to unequivocally identify AD susceptibility genes have been very challenging due to the complex genetic nature of the disease. To facilitate AD susceptibility gene discovery, we propose to monitor an AD endophenotype. This endophenotype is the central pathobiologic event in Alzheimer's disease, the regulated intramembrane proteolysis of the beta-amyloid precursor protein (APP) to generate the amyloidogenic beta-amyloid (Abeta) peptide and the APP intracellular domain (AICD). The AICD fragment of APP displays transcriptional activation properties and we will harness this function to monitor APP processing. Genes that modulate APP processing should be considered functional candidate genes and thoroughly investigated biochemically and in association analyses. We are applying for funding to locate genes that modulate APP processing. To identify the genes that modulate APP processing, we propose a general experimental strategy combining existing technologies in a novel manner. Specifically, we will use RNA interference (RNAi) to silence gene expression and monitor changes in APP processing using AICD-mediated reporter gene expression. The genes to be silenced are biologically compelling and plausible positional candidate genes that reside in the two highest priority linkage regions described in our recently complete genome screen for Alzheimer's disease (Blacker et al., 2003). Genes that modulate APP processing may be genetic risk factors for Alzheimer's disease and should be considered high priority AD candidate genes.