# Rescue of synaptic pathology in an Alzheimer's mouse model by enhancing MET receptor tyrosine kinase signaling

> **NIH NIH R21** · UNIVERSITY OF ARIZONA · 2022 · $422,125

## Abstract

Project Summary/Abstract
Alzheimer's disease (AD) imposes an overwhelming socioeconomic burden on our society. Key pathological
hallmarks of the AD brain are degenerating cortical neurons with neurofibrillary tangles, Tau, and Aβ. At the
cellular and functional level, AD is characterized by impaired synaptic function and synapse loss across many
forebrain regions, and is manifested as disrupted synaptic plasticity, learning, memory, and general intellect.
Mouse models recapitulating certain aspects of AD pathology have been extensively employed to study
mechanisms of neural degeneration and assess efficacy of therapeutic interventions. Recent literature
revealed that MET receptor tyrosine kinase, heavily expressed in the excitatory neurons at early
developmental stages yet functions as a synaptic signaling protein in the adult brain, is reduced in AD brain.
Activation of MET initiates a pleiotropic signaling that exerts neurotrophic and neuroprotective effects in
multiple neurodegenerative mouse models. However, how MET signaling affects AD pathogenesis has not
been investigated. The goal of this proposal is to test whether synaptic pathology in an AD mouse model can
be rescued by enhanced MET-mediated signaling. Recent work from this research team showed that MET
signaling in the developing cortical circuits promotes dendritic spine formation and synaptogenesis, refines
circuit connectivity, and controls the timing of excitatory synapse maturation. More intriguingly, preliminary
data using unique ‘humanized’ hMET conditional knockin (cKI) mice created in the PI’s laboratory revealed
altered transcriptome profiles, increased hippocampal long term potentiation (LTP) and enhanced learning and
memory. In addition, elevated MET signaling in adult hippocampal CA1 neurons resulted in enhanced synaptic
transmission and increased spine density indicative of de novo synaptogenesis. These exciting results have
led to the hypothesis that enhancing MET-mediated pleiotropic signaling prior to neurodegeneration in an
amyloid AD mouse model (5xFAD) may rescue the disrupted molecular pathways, reduce pathological
synapse losses, and alleviate the cognitive decline. To address this hypothesis, two specific aims are
proposed to test whether hMET-cKI signaling alleviates molecular and pathological changes (Aim 1) and
mitigates the synaptic loss and cognitive decline (Aim 2) in the 5xFAD mouse model. Impact: The
hypothesized beneficial effects of hMET signaling highlight the potential of an endogenous pleiotropic
developmental molecular signaling as a novel candidate for neurotrophic therapy in AD.

## Key facts

- **NIH application ID:** 10507127
- **Project number:** 1R21AG078700-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Shenfeng Qiu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $422,125
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10507127

## Citation

> US National Institutes of Health, RePORTER application 10507127, Rescue of synaptic pathology in an Alzheimer's mouse model by enhancing MET receptor tyrosine kinase signaling (1R21AG078700-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10507127. Licensed CC0.

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