Alzheimer's disease is invariably accompanied by the deposition of cerebrovascular and cerebral parenchymal beta/A4-amyloid. Evidence suggests that beta/A4-amyloid is not produced by the normal metabolic pathway for the large beta/A4-amyloid precursor protein (APP), and that deposited beta/A4-amyloid may be toxic to the cerebral vessels and neurons in proximity to the deposits. While pathways for amyloidogenesis are not yet identified, some regulatory mechanisms for modulating the expression and metabolism of APP have been defined. Protein kinases (particularly protein kinase C) and lysosomal pH represent two distinct potential targets for the therapeutic modulation of APP processing. Since amyloidogenesis may be a final common pathway in the evolution of Alzheimer disease, these targets represent rational points for potential therapeutic intervention. Using an APP processing assay, various compounds will be rationally chosen and screened for their efficacy in regulating APP processing. These compounds include PKC stimulators, PKC inhibitors, protein phosphatase inhibitors, ionophores, ion channel blockers, lysosomotropic agents, protease inhibitors and putative metabolic enhancers. Where lead compounds exist (as in the cases of PKC activators and inhibitors, protein phosphatase inhibitors, lysosomotropic agents and protein trafficking compounds), derivatives will be examined in order to initiate the determination of structure-activity relationships of the various classes with specific regard to APP processing. Various host cell systems will be used for the assays, including continuous rat pheochromocytoma (PC-12) cultures, genetically engineered cultures enriched in presynaptic nerve terminals, human cortical neuron (HCN-1) cultures, and primary neuronal cultures. An in vivo assay for APP processing in the brain of the freely moving rodent is under development and will be used as a tertiary screen for promising compounds identified in the cell culture assays.
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