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Summary: Treatment of macrophages from six Alzheimer's Disease (AD) patients and 3 non-AD human controls by curcuminoids in vitro was done. Amyloid beta (A§) was measured by monitoring Aß uptake using fluorescence and confocal microscopy. At baseline, the intensity of Aß uptake by AD macrophages was significantly lower compared to control human macrophages and involved surface binding but no intracellular uptake. After treatment of macrophages with curcuminoids, Aß uptake by macrophages of three of the six AD patients was significantly (P<0.001 to 0.081) increased. The studies were repeated with a highly purified synthetic curcumin. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by this curcumin might be a safe approach to immune clearance of amyloidosis in AD brain and is a "lead" for drug development. The proposed work addresses the problem of creating medications for phagocytosis of Aß of innate immune cells, monocyte/macrophages of AD patients and in clearance of Aß plaques by AD patients. The Aims include: 1) chemical synthesis of analogs of potent immunomodulating curcumin agents, 2) examine the most metabolically stable "lead compounds" in the presence of normal and AD macrophages for Aß phagocytosis, 3) test promising compounds in vivo. Drug candidates that emerge will be examined in an iterative process of ever-improving drug development. The ultimate goal of the project is to gain insight into identifying compounds that modulate Aß phagocytosis. This will result in new medications development of use to combat AD.