Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive dysfunction. Current knowledge of the processes leading to AD is still limited, and no effective treatments are available. Because neurodegeneration is associated with injury and activation of innate immune responses in the brain, drugs that could mimic the beneficial aspects of this response are potential therapeutic candidates. The cytokine transforming growth factor (TGF)-?1 is an organizer of the brain's response to injury and has been shown to have neuroprotective effects in models of brain injury and degeneration. Recombinant TGF-?1 has been used to treat various forms of brain injury in vivo but delivery is not suitable for human use. Studies from our lab have demonstrated that TGF-?1 can reduce the overall accumulation of A?, a key factor in AD pathogenesis, in mouse models for AD and in cell culture. Numerous studies have also demonstrated that TGF-?1 is a potent neurotrophic factor, although high-level chronic TGF-?1 production can also be detrimental. Recently, we reported that reduced TGF-?1 expression in vivo or in cultured neurons increases neurodegeneration. Additional studies show that reducing TGF-? signaling in neurons of a mouse model for AD increases A? accumulation and neurodegeneration and that TGF-? receptor expression is reduced in human AD brains. We have identified bioactive small molecule chemical compounds that can activate the TGF-? signaling pathway in hippocampal neurons of mice and that pass the blood-brain barrier. With reporter cell lines for the TGF-? signaling pathway we screened a diverse small molecule drug library and identified several compounds that are able to activate the reporter system in vitro and in TGF-? reporter mice in vivo. The compounds induce specific TGF-?-responsive genes in cell culture consistent with Smad dependent activation of the TGF-? pathway. These chemicals share common properties from which we propose here to derive a lead compound within 5 years. This project includes structure activity relationship analysis of identified active compounds, medicinal chemistry, toxicology and pharmacology in a subcontract with SRI International. Compounds will be tested in neuroprotection and neurotoxicity assays in cell culture and in TGF-? reporter mice in vivo. The two most promising compounds will then be tested in an in vivo model of neurodegeneration and in a mouse model for AD. Part of the in vivo analysis on neurodegeneration will be done in collaboration with researchers at UCSD. At the end of our studies we propose to have for the first time a novel neuroprotective and amyloid reducing investigational new drug based on the TGF-? signaling pathway for testing in patients with AD.