# Elucidating the role of microglia and neurotrophin receptor p75 on neuronal degeneration in frontotemporal dementia

> **NIH NIH K08** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $193,536

## Abstract

Frontotemporal dementia (FTD) comprises a group of early-onset neurodegenerative diseases characterized by
widespread neuronal degeneration in the central nervous system leading to impairment of behavior, language
and cognition. As for other forms of dementias, mechanisms of neurodegeneration are only poorly understood
and curative treatment options still do not exist. There is growing evidence that non-cell-autonomous
mechanisms play an important role during disease development and that microglial cells significantly contribute
to pathologic changes in patients' brains. Microglial cells are strongly activated in the brains of patients with FTD
and their activation appears to be highest in areas of neuronal cell death. Also, imaging studies have
demonstrated that microglial activation begins early during disease development. Thus, it is very likely that
microglia directly contribute to neuronal degeneration in FTD, a role that has surprisingly been understudied in
the field. This K08 career development project sets out to elucidate such microglia-mediated, non-cell-
autonomous mechanisms of neurodegeneration by combining molecular analyses including single-nucleus RNA
sequencing in postmortem brain tissue with a dynamic human stem cell model of FTD using patient-derived
induced pluripotent stem cells (iPSCs). The overall goal of this study is to characterize changes in cellular
programs in neurons and microglia in FTD and to understand if and how patient microglia influence the integrity
of adjacent neurons in this disease. Encouraged by our preliminary data, we hypothesize that the neurotrophin
receptor p75NTR plays has an important role in this context by promoting death of neurons at risk. We also
propose that FTD-patient derived neurons carry an increased susceptibility to cell death that is further aggravated
by glia cells. This study will apply co-culture assays on iPSC-derived FTD and gene-corrected control neurons
in vitro (Specific Aim 1), transplantation of these cells into the brains of immunocompromised mice (Specific Aim
2) and single cell studies on postmortem brain tissue from FTD patients (Specific Aim 3). During the K08 Award
period, the applicant will also receive training in single-nucleus RNA sequencing on human cells and tissues
from patients with FTD. This project will advance our understanding of the role of microglia and neurotrophin
signaling in the pathogenesis of FTD with the long-term goal to better understand and potentially therapeutically
address the underlying mechanisms of this disease.

## Key facts

- **NIH application ID:** 10328957
- **Project number:** 5K08NS116166-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Gunnar Hargus
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $193,536
- **Award type:** 5
- **Project period:** 2021-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328957

## Citation

> US National Institutes of Health, RePORTER application 10328957, Elucidating the role of microglia and neurotrophin receptor p75 on neuronal degeneration in frontotemporal dementia (5K08NS116166-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328957. Licensed CC0.

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