Identification of the Gamma Secretase Active Site

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain. Amyloid plaques are composed of Beta-amyloid peptides (Abeta), which are produced when amyloid precursor protein (APP) is cleaved by Beta-secretase, and then followed by Gamma-secretase cleavage. Gamma-secretase complexes cleave APP differentially generating two products, Abeta40 and Abeta42, the putatively more toxic species. According to the "amyloid cascade hypothesis," Abeta forms a neurotoxic species that triggers a pathological cascade that leads to neurodegeneration. Therefore, therapies that reduce Beta-amyloid peptides, especially Abeta42, may provide effective treatment of AD. Through detailed biochemical characterization, this study aims to: 1) Synthesize distinct photoreactive, peptidomimetic g-secretase inhibitors which will help isolate the active site proteins of g-secretase, 2) Identify novel proteins that putatively contribute to the active site of g-secretase, and 3) Validate and characterize identified proteins related to g-secretase activity. These investigations will facilitate the development of selective gamma-secretase inhibitors for the treatment of Alzheimer's disease. [unreadable] [unreadable]