# Novel Wnt activators for Alzheimer's disease therapy

> **NIH NIH R21** · MAYO CLINIC  JACKSONVILLE · 2020 · $430,375

## Abstract

PROJECT SUMMARY
 Alzheimer’s disease (AD) is characterized by the presence of amyloid-β (Aβ) and tau pathologies leading to
synaptic dysfunction and neurodegeneration. Despite multiple strategies targeting Aβ 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 Aβ 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 Aβ and tau. Wnt/β-catenin signaling
is an essential pathway that regulates numerous cellular processes including cellular survival. In the brain, Wnt/β-
catenin signaling not only inhibits the Aβ production and tau hyperphosphorylation, but also enhances synaptic
plasticity, neuronal survival and neurogenesis. Wnt/β-catenin signaling is diminished by multiple pathogenic
pathways in AD brain. As such, restoring Wnt/β-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/β-catenin signaling by stabilizing Wnt co-receptor LRP6. Importantly, the leading compound
displays great potency (EC50 less than 1 µM) 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.

## Key facts

- **NIH application ID:** 10055241
- **Project number:** 1R21AG065653-01A1
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** YONGHE LI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $430,375
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055241

## Citation

> US National Institutes of Health, RePORTER application 10055241, Novel Wnt activators for Alzheimer's disease therapy (1R21AG065653-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10055241. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*