Alzheimer?s disease (AD) is characterized by the presence of amyloid-? (A?) and tau pathologies leading to synaptic dysfunction and neurodegeneration. Despite multiple strategies targeting A? and tau, those targeting synaptic failure and neurodegeneration are limited. To address this gap, we have been exploring multiple neuronal signaling pathways that can promote synaptic plasticity and neuronal survival. While it is increasingly clear that targeting early pathologies such as A? amyloid and tau tangles needs to start early in the disease process as prevention prior to clinical manifestations, strategies that are designed to counteract neurodegeneration can be explored after the disease onset, or perhaps in combination with those targeting A? and tau. Wnt/?-catenin signaling is an essential pathway that regulates numerous cellular processes including cellular survival. In the brain, Wnt/?- catenin signaling not only inhibits the A? production and tau hyperphosphorylation, but also enhances synaptic plasticity, neuronal survival and neurogenesis. Wnt/?-catenin signaling is diminished by multiple pathogenic pathways in AD brain. As such, restoring Wnt/?-catenin signaling represents a unique opportunity for rational AD therapy. In our preliminary studies, we have discovered a series of novel potent Wnt activators. Mechanistically, Wnt activators activate Wnt/?-catenin signaling by stabilizing Wnt co-receptor LRP6. Importantly, the leading compound displays great potency (EC50 less than 1 M) and good pharmacokinetic profiles with high oral bioavailability, and is able to penetrate well into the brain. Moreover, the lead activator greatly improves cognitive function in Alzheimer mouse models in our pilot studies. In the current project, we will determine the therapeutic potential of our lead Wnt activators in patient-specific iPSC-derived neurons and AD mouse models. The identified Wnt activators will be promising leads for the development of novel AD therapy.
Currently, there are no disease-modifying treatments for Alzheimer's disease (AD). The Wnt/?-catenin signaling pathway has emerged as an attractive target for AD therapy. The novel potent Wnt activators to be studies through the proposed efforts will be novel drug candidates for AD prevention and treatment.
