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Summary:
Alzheimer's Disease (AD) is characterized by neuronal atrophy due to soluble Ab peptide Á¡oligomersÁ± and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. Alzheimer's Disease (AD) is characterized by neuronal atrophy due to soluble Ab peptide Á¡oligomersÁ± and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. Since anti- Ab oligomer antibodies block the toxicity of the Á¡Ab oligomerÁ± antigen, we hypothesized that compounds that interfere with Ab oligomer and its antibody binding may also interfere with A´‰ oligomer receptor binding and/or assembly into amyloid fibril. Accordingly, we screened a collection of diverse molecules and found that CNI-1493 binds to A´‰-oligomer and interferes with its assembly and recognition by anti- Ab oligomer antibodies and protect neuronal cells from the toxic effect of soluble Ab oligomers. We next tested CNI-1493 in vivo using 4-month-old TgCRND8 mice overexpressing human amyloid precursor protein (APP). CNI-1493 for a treatment period of only 8 weeks resulted in the dramatic reduction of A´‰ deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87 % reduction in the hippocampus of these animals. In addition, CNI-1493 treatment resulted in a significant reduction in microglial activation in the TgCRND8 mice, as measured by F4/80 expression. Our in vitro analysis of CNI-1493 treatment on APP processing in an APP overexpressing cell line suggests a profound dose-dependent decrease of total A©Â accumulation. This effect appears to be separate from either the production of APP or alteration in ´‰- or ´‹-secretase activities. This study identifies the anti-inflammatory agent CNI-1493 as a very promising candidate for the treatment and prevention of AD in clinical trials. Our long-term objectives are to exploit the therapeutic benefit of CNI-1493. Thus, under Specific Aim 1, we will determine the effective dose range of CNI-1493 in APP transgenic mice. Under Specific Aim 2, we will evaluate the prophylactic benefits of CNI-1493 administration in APP transgenic mice. Under Specific Aim 3, we will test for cognition benefits in CNI-1493-treated APP transgenic mice. Under Specific Aim 4, we will characterize the CNI-induced mechanism of Ab reduction.

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