INTERDISCIPLINARY APPROACH TO ALZHEIMER DRUG DISCOVERY

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Alzheimer disease (AD) is a characterized by the deposition of cerebrovascular and cerebral parenchymal beta/A4-amyloid and progressive deficiency of effective cholinergic neurotransmission. These two features are the focus of the proposed Drug Discovery Group. Investigators in Project 1 will focus on amyloid precursor protein (APP) processing in brain and cerebral vessels, using synthetic APP peptides and recombinant APP holoprotein and fragments as APPases will be purified and characterized. In addition to these enzymological studies, APP processing will be studied in cultured endothelial cells, smooth muscle cells and platelets. Investigators in Project 2 will also use an APP processing assay in intact cultured cells, rationally choosing compounds based on the cell biology of APP and screening the compounds for efficacy in regulating APP processing. Where lead compounds exist, derivatives will be examined in order to determine structure-activity relationships of the various classes of compounds. Various host cell systems and an in vivo assay in the brain of the freely moving rodent will be used as screens. Complementing the cell biology and biochemical approaches of Projects 1 and 2, investigators in Project 3 will seek an in vivo model of cerebral amyloidogenesis, overexpressing in transgenic mice mutant APPs which are likely to favor amyloidogenesis. Progressive deficiency in cholinergic neurotransmission is another prominent feature of AD. Fine molecular and physiological characterization of the cholinergic system forms another focus of Project 3 and is the primary focus of Project 4. Newly developed antibodies that differentiate brain muscarinic receptor subtypes will be used to analyze levels and distributions of subtypes in the basal forebrain, hippocampus, and neocortex of aged humans. Also along this line, Project 4 will provide details regarding the possible therapeutic opportunity offered by manipulation of galanin, a neuropeptide and functional antagonist of cholinergic neurotransmission. The preservation in AD of galaninergic systems, coupled with loss of cholinergic neurons, suggests that galanin antagonists might be clinically useful. A Core Facility will serve to provide scientific support to the Projects of the Drug Discovery Group. Among the functions of the Core will be the provision of recombinant wildtype and mutant APP and APP fragments, synthetic peptides, protein purification and sequencing, and industrial liaison for compound derivatization and large-scale synthesis. Liaison for legal and patent matters will also be provided as well as the facilitation of timely communication among all members of the Group.