Novel Wnt modulators for the treatment of Alzheimer’s disease

Abstract

BackgroundAlzheimer’s disease (AD) is the most common form of age‐related dementia characterized by the presence of amyloid‐β (Aβ) and tau pathologies leading to neurodegeneration and cognitive impairment. Wnt/β‐catenin signaling modulates multiple pathophysiological processes including synaptic plasticity, neuronal survival, neuroinflammation, Aβ production and tau phosphorylation, but this signaling pathway is greatly inhibited in the AD brain. Notably, two SNPs and an alternative splice variant of Wnt co‐receptor LRP6, which result in down‐regulation of Wnt/β‐catenin signaling, are associated with increased risk of developing AD. In addition, apoE4, the strongest risk factor of late‐onset AD, interacts with and decreases cell surface abundance of LRP6 in astrocytes. Studies from our laboratory have demonstrated that the level of LRP6 is significantly downregulated in human AD brains, and that deficiency in LRP6‐mediated Wnt/β‐catenin signaling leads to synaptic abnormalities and amyloid pathology in amyloid model mice. Therefore, LRP6 is an attractive therapeutic target for restoring Wnt/β‐catenin signaling in the AD brain.MethodIn our previous studies, we have discovered niclosamide, an FDA‐approved anthelminthic drug, inhibits Wnt/β‐catenin signaling via promoting LRP6 degradation. Herein, we demonstrated that CI‐994, an analog of niclosamide, exhibits opposite effects on LRP6 level and Wnt/β‐catenin signaling. Following structural optimization, we have generated a series of novel potent Wnt modulators.ResultThe leading compound W2A‐16 displays a good pharmacokinetic profile with high oral bioavailability and brain penetration. Importantly, W2A‐16 significantly activates Wnt/β‐catenin signaling and inhibits tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids. Moreover, W2A‐16 attenuates amyloid pathology and gliosis and improves cognitive function in 5xFAD amyloid model mice. Further, W2A‐16 suppresses tau phosphorylation and neuroinflammation, attenuates body weight loss, and improves the survival of PS19 tauopathy mice.ConclusionTogether, these findings demonstrate that W2A‐16 is a strong drug candidate for AD therapy.

A novel histone deacetylase inhibitor W2A-16 improves the barrier integrity in brain vascular endothelial cells

“…We have reported that W2A-16 effectively mitigates amyloid pathology and cognitive decline in 5xFAD amyloid model mice. Furthermore, we have showed that W2A-16 reduces tau phosphorylation and neuroinflammation in PS19 tauopathy mice ( Li et al, 2022 ). Moreover, our recent unpublished data indicate that W2A-16 is also a novel potent class I HDAC inhibitor.…”

“…However, the molecular mechanisms underpinning BBB maintenance and governing gene transcription remain elusive. We have developed a novel Wnt activator named W2A-16 ( Li et al, 2022 ), which is documented in World Intellectual Property Organization (WIPO) PatentScope database (WO2021007313). We have reported that W2A-16 effectively mitigates amyloid pathology and cognitive decline in 5xFAD amyloid model mice.…”