Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitivedysfunction. Current knowledge of the processes leading to AD is still limited, and no effective treatments areavailable. Because neurodegeneration is associated with injury and activation of innate immune responsesin the brain, drugs that could mimic the beneficial aspects of this response are potential therapeuticcandidates. The cytokine transforming growth factor (TGF)-Bl is an organizer of the brain's response toinjury 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 suitablefor human use.Studies from our lab have demonstrated that TGF-B1 can reduce the overall accumulation of AB, a keyfactor in AD pathogenesis, in mouse models for AD and in cell culture. Numerous studies have alsodemonstrated that TGF-B1 is a potent neurotrophic factor, although high-level chronic TGF-B1 productioncan also be detrimental. Recently, we reported that reduced TGF-B1 expression in vivo or in culturedneurons increases neurodegeneration. Additional studies show that reducing TGF-B signaling in neurons ofa mouse model for AD increases AB accumulation and neurodegeneration and that TGF-B receptorexpression is reduced in human AD brains.We have identified bioactive small molecule chemical compounds that can activate the TGF-B signalingpathway in hippocampal neurons of mice and that pass the blood-brain barrier. With reporter cell lines for theTGF-B signaling pathway we screened a diverse small molecule drug library and identified severalcompounds that are able to activate the reporter system in vitro and in TGF-B reporter mice in vivo. Thecompounds induce specific TGF-p-responsive genes in cell culture consistent with Smad dependentactivation of the TGF-B pathway. These chemicals share common properties from which we propose here toderive a lead compound within 5 years. This project includes structure activity relationship analysis ofidentified active compounds, medicinal chemistry, toxicology and pharmacology in a subcontract with SRIInternational. Compounds will be tested in neuroprotection and neurotoxicity assays in cell culture and inTGF-B reporter mice in vivo. The two most promising compounds will then be tested in an in vivo model ofneurodegeneration and in a mouse model for AD. Part of the in vivo analysis on neurodegeneration will bedone in collaboration with researchers at UCSD. At the end of our studies we propose to have for the firsttime a novel neuroprotective and amyloid reducing investigational new drug based on the TGF-B signalingpathway for testing in patients with AD.
| Miller, Zachary A; Rankin, Katherine P; Graff-Radford, Neill R et al. (2013) TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry 84:956-62 |
