Drug Agonists of TGFbeta Signaling to Treat Alzheimer's

Stanford University, Stanford CA

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease 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 in is associated with injury and an 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)-b1 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-b1 has been used to treat various forms of brain injury in vivo but delivery is not suitable for human use. [unreadable] [unreadable] Studies from our lab have demonstrated that TGF-b1 can reduce the overall accumulation of Ab, a key factor in AD pathogenesis, in mouse models for AD and in cell culture. Numerous studies have also demonstrated that TGF-b1 is a potent neurotrophic factor although high-level chronic TGF-b1 production can also be detrimental. Recently, we reported that reduced TGF-b1 expression in vivo or in cultured neurons increases neurodegeneration. Additional preliminary studies presented here show that reducing TGF-b signaling in neurons of a mouse model for AD increases Ab accumulation and neurodegeneration and that the brain is a major site of TGF-b signaling in the mouse. [unreadable] [unreadable] We have started to search for small molecule chemical compounds that can activate the TGF-b signaling pathway. With reporter cell lines for the TGF-b signaling pathway we screened a diverse small molecule drug library containing and identified several compounds that are able to activate the reporter system in vitro and early tests indicate that at least one may be active in vivo. We propose to screen a larger chemical library for compounds that activate TGF-b signaling in vitro to test their activity in AD-relevant cell culture assays and mouse models and in a reporter mouse for the TGF-b signaling pathway. This combined screening approach should allow us to identify compounds that have activity in vivo to test the hypothesis that chemical activators of the TGF-b signaling pathway can be used to delay or reduce neurodegeneration and AD-like disease in mice. Together with our collaborators at the high-throughput screening facility at Stanford and at SRI International we expect to find such compounds that activate the TGF-b signaling pathway and test them in vivo in TGF-b reporter mice and in mouse models for AD. After the completion of the proposed studies we hope to be in a position to initiate lead optimization studies with non-profit or commercial collaborators. This would for the first time bring a novel neuroprotective and amyloid reducing drug based on the TGF-b signaling pathway towards testing in AD. [unreadable] [unreadable]