# Application of single cell sequencing to study astrocyte-mediated neuronal degeneration in a stem cell model of frontotemporal dementia

> **NIH NIH R03** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $81,000

## Abstract

Despite the high prevalence of dementias worldwide, mechanisms of neurodegeneration are only poorly
understood and thus, curative treatment options still do not exist. There is growing evidence that non-cell-
autonomous mechanisms of neuronal degeneration play an important role during disease development and
that both neurons and astrocytes could significantly contribute to pathologic changes in patients' brains. In
this study, we will apply single cell sequencing to analyze astrocyte-mediated effects on neurons in a stem
cell model of frontotemporal dementia (FTD) and hypothesize that astrocytes from patients with FTD have
detrimental effects on adjacent neurons in vitro and in vivo. We will generate neurons and astrocytes from
patient-derived induced pluripotent stem cells carrying the N279K mutation in the gene encoding the protein
tau (MAPT) as a model for FTD. In parallel, we will differentiate neurons and astrocytes from CRISPR/CAS9-
gene corrected isogenic control (Ctrl) stem cells that carry an identical genetic information as the parental
MAPT N279K cells except for the disease-causing mutation. FTD and Ctrl neurons will be co-cultured with
either FTD or Ctrl astrocytes and effects on neuronal survival and whole transcriptome profiles will be
determined. Astrocyte-mediated changes in gene expression will be evaluated at a single cell level by
applying single cell RNA sequencing on co-cultured neurons and astrocytes. We will put a special emphasis
on the role of the cytoplasmic protein MAGEH-1 in this context, which is known to bind to the nerve growth
receptor (p75NTR) and which we found to be upregulated in FTD iPS cell-derived neurons along with
p75NTR in an attempt to prevent further damage to compromised cells. We will also determine the effects of
FTD astrocytes in vivo by transplanting FTD astrocytes or Ctrl astrocytes with neurons into the brain of
immunocompromised mice. Grafts will be examined 10 weeks after transplantation histologically and via ex
vivo single cell RNA sequencing to evaluate cell survival and cell death as well as single cell RNA expression
profiles in vivo. We believe that this project has strong potential to better understand the role of astrocytes on
neuronal degeneration in FTD.

## Key facts

- **NIH application ID:** 9933111
- **Project number:** 5R03NS112785-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Gunnar Hargus
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $81,000
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933111

## Citation

> US National Institutes of Health, RePORTER application 9933111, Application of single cell sequencing to study astrocyte-mediated neuronal degeneration in a stem cell model of frontotemporal dementia (5R03NS112785-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9933111. Licensed CC0.

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