# Drug repurposing for Alzheimer’s disease-related inflammation caused by a TBI

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2024 · $191,250

## Abstract

PROJECT SUMMARY/ABSTRACT
The CDC estimates that at least 200,000 older Americans (> 65 years) will have a traumatic brain injury (TBI)
each year, primarily caused by a closed head injury (CHI) from a fall. The aged brain, with Alzheimer’s disease
neuropathological changes, has significant reactive microglia and astrocytes and other markers of
neuroinflammation. An acquired brain injury can further exacerbate this state of reactive gliosis and
neuroinflammation. Alzheimer’s disease poses a significant therapeutic challenge, given that pathology can
develop over decades. However, we believe that it is an obtainable therapeutic goal to prevent the worsening
of neuroinflammation caused by an acquired brain injury in those at risk for developing Alzheimer’s disease .
Control of neuroinflammation following the TBI in older adults is a promising avenue for improving patient
outcomes. However, no drug has earned FDA approval for specific use in mild TBI. There is also limited
evidence to guide the repurposing of FDA-approved drugs that target neuroinflammation for this unique
population. Broad-spectrum immunosuppressants are not advisable and, while selective biologics (such as
anti-TNF) are promising, they also come with the risk of increasing infection, which is problematic in an older
adult population at risk for infections. Our goal is to identify targeted immunomodulatory (not,
immunosuppressants) with a high benefit-to-risk ratio. We recently identified the commonly prescribed
antibiotic, Azithromycin (AZM), as an immunomodulatory agent with neuroprotective effects in spinal cord
injury. Because of its safety profile, AZM is frequently prescribed as a prophylactic treatment in several
conditions and broadly administered in at-risk disease populations. This proposal aims to provide proof-of-
principal data for AZM as a safe and effective neuroinflammatory modulatory drug. We will test the central
hypothesis that AZM can alter neuroinflammation and improve cognitive outcomes following a CHI in an
APP/PS1 KI mouse model of Alzheimer’s disease-related pathology in the following two specific aims (SA).
 SA1: Define the immunomodulatory dose-dependent effect of AZM in 8-month-old APP/PS1 KI mouse
 model following a CHI.
 SA2: Evaluate the effects of AZM on CHI-induced behavioral and Alzheimer’s disease-related
 neuropathology in 8-month-old APP/PS1 KI mice.
This proof-of-concept study could establish AZM as a safe and well-tolerated FDA-approved drug to reduce
damage and speed recovery in the fragile older brain following a CHI. Once the feasibility of AZM treatment
has been established, new areas of drug development and clinical research with the potential to more quickly
develop a new drug to slow the devastating effects of Alzheimer’s disease can be created.

## Key facts

- **NIH application ID:** 10782489
- **Project number:** 5R21AG077495-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** ADAM D BACHSTETTER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $191,250
- **Award type:** 5
- **Project period:** 2023-02-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10782489

## Citation

> US National Institutes of Health, RePORTER application 10782489, Drug repurposing for Alzheimer’s disease-related inflammation caused by a TBI (5R21AG077495-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10782489. Licensed CC0.

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