# Identifying T cell determinants of heritable Frontotemporal dementia

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $604,649

## Abstract

Project Summary/Abstract
Alzheimer’s disease and the related disorder Frontotemporal dementia (FTD) represent a major financial and
emotional burden to society, but to date no preventative strategies have been developed. While a critical barrier
to improving the quality of life for people suffering from or caring for those with FTD is a lack of mechanistic
understanding of the causes, there is substantial evidence that T cell dysfunction and the balance of T cell
subsets contributes to disease pathogenesis and may explain heterogenous patient outcomes. This suggests
that strategies to stabilize patient T regulatory cells and/or reduce levels of pro-inflammatory Th17 cells are likely
to benefit FTD patients. A key knowledge gap is how environmental signals such as those derived from the gut
microbiome interact with common FTD genotypes to affect T cell function and disease progression. A repeat
expansion in a non-protein-coding region of the gene C9ORF72 is the most common cause of FTD and the
related motor neuron disorder Amyotrophic lateral sclerosis, responsible for approximately 10% of all diagnoses.
The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are
implicated in neural degeneration. The expansion is transcribed into a long repetitive RNA that sequesters RNA
binding proteins before being translated into aggregate-prone repetitive dipeptide proteins. The mutation also
leads to reduction of the endogenous C9ORF72 gene product that functions in endo-lysosomal pathways and
suppresses systemic and neural inflammation. In preliminary work, we have demonstrated that signals derived
from gut bacteria modify the penetrance and expressivity of neural inflammation in mice with reduction of
C9orf72. Additionally, we have established that C9orf72 functions in cells of both the myeloid and lymphoid
lineages to oppose autoimmunity and neural inflammation. The first AIM of this proposal will seek to elucidate
how C9orf72 functions within T cells to govern cell fate choice. The second AIM of this proposal will seek to
determine how a C9orf72 genotype influences pathogenic T cell responses to intestinal microbes and to
determine the extent to which pro-inflammatory cytokine Interleukin-17A participates in neural inflammation when
C9orf72 levels decline. In the third AIM of this proposal, we will evaluate whether the changes in T cell fate and
function we observe in our animal model also occur in humans with a C9ORF72 mutation that converts to FTD
but not in carriers of the mutation that are protected from neurological disease. The proposed studies have
potential to shed mechanistic insight into regulation of FTD/ALS disease course by T cells and to identify novel
prognostic markers and therapeutic targets for Alzheimer’s disease and related dementias.

## Key facts

- **NIH application ID:** 10804946
- **Project number:** 1R01AG085316-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Aaron Burberry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $604,649
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804946

## Citation

> US National Institutes of Health, RePORTER application 10804946, Identifying T cell determinants of heritable Frontotemporal dementia (1R01AG085316-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10804946. Licensed CC0.

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