Small molecule Wnt modulators to treat Alzheimer’s
Mayo Clinic researchers have developed a small molecule modulator for use in treating and preventing a variety of Wnt-related conditions such as Alzheimer’s Disease (AD) and other neurodegenerative disorders, traumatic and ischemic brain injury, as well as bone loss disorders.
Wnt/β-catenin signaling is crucial for synaptic plasticity, neuronal survival, and neurogenesis. Relevant to AD, activation of Wnt/β-catenin signaling inhibits Aβ production and tau hyperphosphorylation, two events central to the pathogenesis of AD. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brains through multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents an attractive strategy for the rational design of novel AD therapies. In preliminary studies, a series of novel Wnt modulators have been developed. The lead compounds display great potency (EC50< 500 nM) in activation of Wnt/β-catenin signaling, good pharmacokinetic profiles with high oral bioavailability and brain penetration. Importantly, the lead modulator W2A-16 significantly suppresses tau phosphorylation and improves cognitive function in the Alzheimer mouse models. Moreover, W2A-16 greatly prevents body weight loss and enhances the survival ofPS19 tau transgenic mice.