# Investigating the role for Utrophin in age-related decline of the Merkel lineage

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $337,225

## Abstract

SUMMARY
Alzheimer’s disease (AD) is the most common form of dementia with an estimated 6.5 million patients aged 65
and older being affected in the US. Current FDA-approved therapies for AD include anti-amyloid antibody
infusion therapy to delay disease onset or cholinesterase inhibitors and glutamate regulators to treat cognitive
symptoms. However, these treatment options carry severe side effects and are not effective at stabilizing
cognitive symptoms or curing the disease. Collectively, these observations underscore an unmet medical need
for novel targets that allow for efficacious eradication of the neurodegenerative features and symptoms related
to AD. Interestingly, AD patients are known to also suffer from deficits in somatosensory perception, including
our sense of gentle touch. However, these deficits are postulated to be masked by the severe cognitive
dysfunction observed in the AD brain. Nevertheless, our sense of gentle touch enables numerous behaviors
fundamental to human existence, allowing us to eat, communicate and survive and is encoded by cutaneous
Merkel cells, a mature neuroendocrine lineage of mechanoreceptors that are innervated by slowly adapting
type I afferents. The overarching goal of our active R01AG073874 grant is to define the cellular and molecular
basis for maintenance of the Merkel lineage in the adult skin and leverages key preliminary data from our
laboratory that comprehensively chronicles a dramatic decline in Merkel cell numbers and tactile acuity in
human and murine skin across the lifespan. Since aging is a risk factor for AD onset and deficits in tactile
acuity, and somatosensory deficits, including loss of gentle touch, are a reported co-morbidity in AD patients,
we postulated that convergent mechanisms may govern these pathologies in the central nervous system (AD)
and the periphery (Merkel cells). In support of this idea, our new preliminary data shows i) highly accelerated
loss of cutaneous Merkel cells in four-month-old 5XFAD transgenic mice, a widely utilized mouse model of AD,
and ii) expression enrichment for two AD-associated proteins, App and Psen1, in epithelial progenitors for the
Merkel lineage. Collectively, these observations raise the hypothesis that AD-related mutations harbored in
5XFAD mice may also be relevant for Merkel cell stability. We will test this hypothesis with a comprehensive
assessment of the impact of AD mutations on Merkel cell numbers and epithelial progenitor function in the
skin. Our preliminary data also highlight the need to leverage 5XFAD mice to identify putative convergent
mechanisms of disease etiology between age-associated AD and Merkel cell loss. We will address this need
by creating a multi-omics atlas of AD at single-cell resolution in brain and skin tissues at critical age points
across the murine lifespan correlating with pre- and post-AD onset in humans. These efforts will support our
long-term goal to uncover rare cell types with unknown markers of AD and o...

## Key facts

- **NIH application ID:** 10952725
- **Project number:** 3R01AG073874-04S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** David Michael Owens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $337,225
- **Award type:** 3
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10952725

## Citation

> US National Institutes of Health, RePORTER application 10952725, Investigating the role for Utrophin in age-related decline of the Merkel lineage (3R01AG073874-04S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10952725. Licensed CC0.

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