# New role(s) for IRF5 as a regulator of tau accumulation in Alzheimer’s disease

> **NIH NIH R21** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2022 · $209,375

## Abstract

PROJECT SUMMARY/ABSTRACT
Tau pathology is central to the development of Alzheimer’s disease (AD) and its clinical progression, hence
current therapeutic efforts are directed at reducing tau burden in the brain by immunotherapy. The initial
seeding and deposition of tau is associated with an early inflammatory response, in both human disease and
mouse models of AD. The immune system responds rapidly to the accumulation of tau and other aggregated
proteins, in order to clear them from the brain and prevent further immune activation. However, if clearance is
unsuccessful, the accumulation of aggregated proteins will likely lead to excessive inflammation, and
paradoxically, more tau spreading and accumulation. This complex relationship between tau pathology and
inflammation is still not fully characterized. We identified the transcription factor interferon regulatory factor 5
(IRF5) as a new mediator of microglia activation in response to pathological tau. We found that IRF5 is
activated, i.e. nuclear-localized, in microglia after stimulation with pathological tau, and IRF5 expression is
increased in brain tissue from AD patients as compared to healthy donors. Further, aged mice lacking IRF5
showed increased accumulation of soluble tau. Together, these data suggest a new role for IRF5 in microglia
immunosurveillance of aggregated, pathological tau. The premise of this application is that IRF5-mediated
signaling in microglia is a critical step in regulating tau accumulation. In this proposal, we will 1) Test the
hypothesis that IRF5 is required for immunosurveillance of pathological tau in the brain, 2) Determine whether
therapeutic inhibition of IRF5 protects P301S mice from disease onset, progression and neurodegeneration,
and 3) Determine the mechanism(s) by which IRF5 participates in the immune response against pathological
tau. Successful completion of these studies will 1) identify a new factor – IRF5 – that contributes to
immunosurveillance of pathogenic stimuli in the brain and 2) determine whether IRF5 is a viable therapeutic
target for AD and tauopathies.

## Key facts

- **NIH application ID:** 10485250
- **Project number:** 5R21AG070682-02
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Betsy J Barnes
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2021-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485250

## Citation

> US National Institutes of Health, RePORTER application 10485250, New role(s) for IRF5 as a regulator of tau accumulation in Alzheimer’s disease (5R21AG070682-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10485250. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*