Alzheimer's disease (AD) patients manifest severe impairment of memory and learning disorder, the most important functions of the human brain. More than 10 million people suffer from this devastating disease. To elucidate its pathogenesis and develop specific therapy is an urgent issue. The beta amyloid peptide is a major constituent of senile plaques, one of the hallmarks of AD pathology, and has been implicated in its pathogenesis. This peptide is the cleavage product of a larger precursor, APP, which serves as a cell-surface receptor coupling to Go, a neuron-specific member of the signal-transducer G protein family. In familial AD (FAD), a point mutation occurs in the transmembrane domain of APP. Using a chemically defined system, my preliminary study has shown that the FAD-linked APPs (FAD-APPs) have constitutively active receptor functions to active Go. The long-term goal of the proposed project is to fully understand the role of FAD-APPs in the pathogenesis of AD.
Its specific aims are (i) to examine the hypothesis that FAD-APPs are receptors that activate Go and the Go-linked cascade, especially adenylate cyclase (AC)-cAMP response element (CRE) system in intact cells, in a constitutive manner, and (ii) to establish a system for observing the ligand-dependent activation of Go by APP in intact cells. This project is expected to provide valuable new insight into the intracellular pathophysiology occurring in AD. Dysregulation of AC and CRE by FAD-APP and Go will be given particular attention, because the CRE system is pivotal in long-term memory formation.
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