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.

PROJECT NARRATIVE This project will investigate the potential of the commonly prescribed antibiotic, Azithromycin, as an immunomodulatory agent to speed recovery and reduce injury-exacerbated Alzheimer’s disease neuropathological changes following an acquired brain injury. Hypothesis-based drug repurposing of azithromycin will provide a novel therapeutic agent for use in Alzheimer’s disease, with a reduced time frame for the drug development.