CAVEOLAE FOR THE PROCESSING OF APP

DESCRIPTION: (Applicant's abstract) Alzheimer's disease (AD) is the major cause of memory loss and dementia. Senile plaques and paired helical filaments are pathological hallmarks of AD brains. A beta peptide, the principal protein component of senile plaques, is generated by the processing of amyloid precursor protein (APP). Understanding the molecular mechanism whereby APP is processed to generate A beta peptide is crucial to unraveling the mechanism of senile plaque. Alpha-secretase cleaves APP in the middle of A beta peptide an , therefore, precludes its production. The present project will focus on the cellular and molecular mechanisms by which APP is processed by alpha-secretase. Our studies are based on our recent report that indicated APP enrichment in caveolae, a specialized domain on the cell surface membranes consisting of caveolins, where alpha- secretase cleavage of beta-APP takes place. Specific aims will test the following hypothesis: (1) Astrocytes possess caveolae and caveolin; (2) Increased caveolin production in astrocytes will increase a alpha- secretase processing of a Swedish beta-APP mutant found in FAD and; (3) Caveolin expressing will increased wild-type beta-APP processing at an alpha-secretase site on neuronal cells. These studies will clarify the precise location of beta-APP processing by alpha-secretase and may help develop a specific therapeutic strategy to prevent AD. Augmentation of caveolin expression may provide a unique approach to alter the processing pattern of beta-APP from the amyloidogenic beta/gamma to the non-amyloidogenic alpha-secretase. These studies would generate a new line of research for preventing the generation of toxic amyloid peptide in vivo.