Role of Lipid Rafts in Gamma Secretase Processing of APP

Alzheimer’s disease (AD) is the major cause of dementia in the elderly. Mutations in genes encoding Presenilins and Amyloid Precursor Protein (APP) cause early onset AD. These mutant proteins increase the production of toxic beta-amyloid peptides (Aβ), which accumulate in the brains of individuals with AD. Production and accumulation of Aβ are central events in AD pathogenesis. This proposal seeks to investigate the regulation of Aβ production. Aβ is released from truncated APP by the action of “y-secretase”, composed of Presenilins and three other proteins. Specialized microdomains of cellular membranes, called lipid rafts, seem to play important role in Aβ production. Dr. Thinakaran seeks to investigate how y-secretase complex is selectively targeted to lipid rafts. He also proposes to examine the regulation of y-secretase complex and APP by a variety of molecular and cell biological approaches. A better understanding of the relationship between y-secretase and lipid rafts will shed more light on the mechanisms involved in Aβ production. Information stemming from the biochemical, molecular and cellular investigations will likely be critical in developing novel and rational strategies for therapeutic intervention for AD aimed at reducing Aβ burden.