Deposition of the beta amyloid protein in the brain is a pathological hallmark of Alzheimer's disease (AD). The goal of this proposal is to understand the molecular basis of recently defined neurodegenerative effects of beta amyloid. The minimal peptide structural requirements for beta amyloid neurotoxic activity will be determined and used to synthesize small active peptides for receptor binding studies in cultured hippocampal neurons. The newly identified serpin-enzyme complex (SEC) receptor that binds beta amyloid and substance P will be characterized in hippocampal neurons. To determine the role of the SEC receptor, natural and artificial SEC receptor ligands will be tested for effects on beta amyloid neurotoxic activity. The cellular effects of beta amyloid which follow binding involve changes in cytoskeletal integrity. The AD-associated A68 protein, an abnormally phosphorylated tau protein, is induced in hippocampal neurons by beta amyloid. Epitope mapping and direct sequencing will be performed to determine if induction of A68 in culture is due to the same post- translational modification of tau that occurs in the AD brain. The mechanism of A68 induction will be examined by determining if beta amyloid stimulates protein kinase activity. The role of A68 induction and cytoskeletal disruption in the neurodegenerative process will be assessed by electron microscopy and immunogold labeling of cytoskeletal proteins. Tachykinin peptides inhibit the neurotoxicity of beta amyloid in culture and in vivo in the adult rat brain. The mechanism of this effect will be initially examined by determining if it involves either the tachykinin NK1 receptor or the serpin receptor. The peptide structural requirements for inhibiting beta amyloid neurotoxicity will be determined using deletions, substitutions, and modifications of the substance P peptide. The studies outlined in this proposal will characterize a potential model system for the pathogenesis of AD and may lead to the rational design of new therapeutic interventions for AD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Murphy, Diane
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Children's Hospital Boston
United States
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