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The accumulation of b-amyloid peptide (Ab) appears central to AD pathogenesis; large efforts have been directed at understanding and interfering with Ab production or aggregation. Dr Wyss-Coray has identified a novel brain factor, Transforming Growth Factor b1 (TGF-b1), that may be involved in Ab clearance and is known to be neuroprotective. In animal studies, treatment with this factor results in a remarkable reduction in b amyloid in the brain. In addition, TGF-b1 stimulated the removal of b-amyloid by a specific type of neuronal cell known as microglia. These novel results demonstrate that TGF-b1 is an important modifier of b-amyloid deposition in vivo and suggest that TGF-b1 may promote a process that actively removes Ab from brain. The overall aim is to identify lead small molecules that mimic TGF-b1’s Ab reducing and neuroprotective effects in CNS cell cultures. Dr Wyss-Coray will screen a library of 250,000 compounds in a high-throughput TGF-b reporter cell assay for their ability to activate reporter genes in glial cells or TGF-b1 knockout fibroblasts and their specificity in reporter assays. Lead compounds from the screens will be selected for further experiments in subsequent years and will be tested in Ab clearance assays, neuronal survival tests, and transgenic mouse models of AD. If successful this program may lead to the discovery of a novel class of disease- modifying, small- molecules that are neuroprotective and remove b- amyloid from brain.