FUNCTION OF AN ALZHEIMER DISEASE-RELATED PROTEIN

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DESCRIPTION: (Adapted from Applicant's Abstract): The goal of this proposal is to determine the normal function of synelfin, a neuronal protein abundant in the adult vertebrate telencephalon. Synelfin has been independently isolated from several species, including humans, where it has been referred to as NACP (the Non-Amyloid beta-Component Precursor) to indicate its relationship to a novel peptide recently purified from amyloid plaques in Alzheimer Disease (AD). Studies in songbirds suggest that this highly-conserved protein has a specific but yet-undefined role in the normal regulation of synaptic plasticity. To gain insight into the normal function of synelfin, three research aims are proposed: 1) conduct biochemical studies to test the hypothesis that synelfin has a functional relationship to apolipoproteins, as suggested by observation of conserved structural features. Normal and mutated forms of synelfin protein will be expressed in E.coli and analyzed for their interactions with phospholipids, using the well-characterized behavior of apoliopoproteins as a point of comparison. 2) determine the structural elements in the protein responsible for its accumulation at presynaptic terminals. Mutated DNA constructs will be introduced into primary cultured hippocampal neurons, and the encoded proteins will be localized by immunofluorescence. These studies may give insight into the apparent modular structure of the protein, and help in the design of experiments to identify other proteins with which synelfin interacts. 3) overexpress the synelfin protein in transgenic mice and assay the effect on neuroanatomy and neurological function. This will test the hypothesis whether a constitutive increase in synelfin will promote the development of Alzheimer-like neuropathology, or alter developmental or behavioral processes that depend upon neural plasticity.