Interdisciplinary Approach to Alzheimer Drug Discovery

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DESCRIPTION (provided by applicant): The history and current activity of this Program Project attest to its focus on discovery of druggable anti-Abeta oligomer targets by identifying the molecular bases for the phenomena that appear important for Abeta oligomerization and accumulation (e.g., protein folding, protein levels, etc.). The theme of all Projects in the A2 revision of this competitive renewal focuses on lipoprotein regulation of APP and Abeta metabolism at the cell surface. Growing evidence indicates that low and high density lipoproteins control two limbs of the APP/Abeta metabolic scheme: Apolipoproteins E and J modulate Abeta clearance via a variety of surface receptors, while LDL and HDL activate signalling pathways via the low density lipoprotein receptor-like protein (LRP) that feed back on the cell surface and cause activation or inhibition of APP metabolism by alpha-secretase ("ectodomain shedding"). Major questions posed by each Project are: (Project by Gandy) Statins activate alpha-secretase via ROCK. How do lipoproteins modulate this signal following binding to LRP? What are the phospho-state-specific modulators of APP ectodomain shedding? (Project by Ghiso): How do conformational transitions of Abeta and interactions of oligomeric Abeta with Apolipoproteins/Apolipoprotein receptors affect protein catabolism within brain cells, resulting in Abeta accumulation and the concomitant formation of the amyloid deposits seen in Alzheimer's? (Project by Buxbaum): What role(s) do the major ApoE receptors play in Abeta metabolism? (Project by Martins):. Can ApoE isoform-specific effects on Abeta clearance be demonstrated in vitro or in vivo? What is the role of ApoE protein level in brain or in the circulation? These questions will be answered using a highly collaborative approach and a range of experimental systems, including purified proteins, expression of foreign genes in primary CNS cells, and genetic induction of excessive or deficient levels of CNS proteins. Ultimately, data from such approaches will inform the development of effective anti-amyloid agents, which, in turn, will provide the ultimate test of the role of Abeta oligomerization in Alzheimer's disease.