# Bacterial triggers of neural inflammation.

> **NIH NIH R03** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $161,000

## Abstract

Project Summary/Abstract
Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that starts with alterations in
behavior or language and culminates in severe impairment of memory and cognition. While in most cases the
etiology of FTD is unclear, a hexanucleotide repeat expansion in C9ORF72 is the most common inherited cause
of FTD and the related motor neuron disease Amyotrophic lateral sclerosis (ALS). Incomplete penetrance of the
C9ORF72 mutation in families with high prevalence of FTD/ALS indicates that either genetic or environmental
factors modify disease risk. Previously we found that mice with loss of function mutations in C9orf72 experienced
the neural inflammatory features of FTD and died if they were raised in environments that displayed distinct
microbial communities in their gut. Sequencing of fecal matter from environments where C9orf72 mutant mice
displayed divergent health outcomes allowed us to nominate 40 candidate bacterial species that were enriched
in the environments where animals got sick and died. In the first Aim of this proposal, we will use our proxy
macrophage cytokine release assay to determine which of these 40 candidate bacterial species activate an
inflammatory response so that 2-3 bacterial strains can be nominated for functional follow-up. In the second Aim,
we will transplant pro-inflammatory bacteria into germ-free C9orf72 mutant mice to identify strains that trigger
neural inflammation and loss of CNS immune privilege. Our studies will help to identify environmental factors
that credibly contribute to observed heterogeneity in FTD patient phenotype and clinical outcome and provide
insight towards selection of dementia patients most likely to benefit from therapies that target the gut microbiome.

## Key facts

- **NIH application ID:** 10747981
- **Project number:** 5R03AG080175-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Aaron Burberry
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $161,000
- **Award type:** 5
- **Project period:** 2022-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747981

## Citation

> US National Institutes of Health, RePORTER application 10747981, Bacterial triggers of neural inflammation. (5R03AG080175-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10747981. Licensed CC0.

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