# Molecular Mechanism of Wnt/Planar Cell Polarity Signaling

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $422,500

## Abstract

Abstract
Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder during aging and an unmet
medical challenge. AD is a complex multi-factorial disease clinically characterized by a decline in cognitive
function and pathologically defined by the accumulation of extracellular β-amyloid (Aβ) plaques and intracellular
neurofibrillary tangles (NFTs). AD can be caused by both genetic defects and environmental factors and genetic
mutations and risk factors have been identified that are either causal or modify the disease progression. Cellular
and molecular alterations in the neuronal, astroglial, microglial/immune, and endothelial/vascular cells that
modify the AD pathological hallmarks in the brain have been the focus of studies. The Wnt signaling pathways
have been found to be involved causatively in the pathogenesis of AD. However, most of the research has been
focused on the Wnt/b-catenin pathway. The role of the Wnt/planar cell polarity (PCP) signaling pathway in AD,
though important, was understudied. The Wnt/PCP pathway is a highly conserved regulator of cellular orientation
within the plane of an epithelium and has been found to be essential for brain development and function.
Intriguingly, the Wnt-PCP pathway regulates axon outgrowth rather than neuronal polarity during brain
development of both vertebrates and Drosophila. Despite the conservation of Wnt/PCP signaling from Drosophila
to mammals, PCP regulation in vertebrates is more complex, functionally diverse and requires additional
regulatory schemes and vertebrate-specific PCP component such as Ror2. It has been found that PCP signaling
components play essential roles in glutamatergic synapse formation in development and Wnt/PCP signaling
interacts with the amyloid precursor protein (APP) that is cleaved to become Aβ and such interaction alters
Wnt/PCP signaling, which drives tau pathology and neuronal death causing AD. The majority of AD clinical trials
have focused on reducing Ab load and unfortunately, these trials have been unsuccessful so far. Thus, there is
an urgent need to pursue other disease modifying mechanisms and therapies. In our previous studies before
and after the support of the parental grant, we have made the novel discovery for the regulation of Vangl2
phosphorylation by Wnt5a and Ror2, which exhibits fundamental difference when flies evolve to mammals. We
will expand our investigation of functional requirement of Vangl2 phosphorylation in vivo in pathogenesis and
progression of AD in two genetic mouse models focused respectively on APP/Ab production (5XFAD Tg6799)
and tau hyper-phosphorylation (PS19). We will also determine the role of APP in Wnt5a-induced PCP
signalosome. In so doing, we will gain critically important new insights into the pathophysiological mechanism
underlying Wnt/PCP signaling in AD, as well as identify potential targets for manipulating Wnt/PCP signaling as
an approach for AD treatment.

## Key facts

- **NIH application ID:** 10288018
- **Project number:** 3R01AR070877-04S1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Yingzi Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $422,500
- **Award type:** 3
- **Project period:** 2017-02-07 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288018

## Citation

> US National Institutes of Health, RePORTER application 10288018, Molecular Mechanism of Wnt/Planar Cell Polarity Signaling (3R01AR070877-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288018. Licensed CC0.

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