# Aging exacerbates trauma-induced immune pathways and neuronal dysfunction

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $352,300

## Abstract

Project Summary
Traumatic brain injury (TBI) is extremely debilitating for the aging community with both increased incidence and
outcome severity within this population. Furthermore, TBI is a strong environmental risk factor for development
of Alzheimer's disease and other dementia related illnesses. The importance of age as a prognostic factor after
TBI has long been recognized but limited studies have been devoted to understand mechanisms that regulate
secondary events that occur after the initial trauma. Even less research has been aimed at studying the
mechanisms of cognitive loss in the elderly. The critical changes that affect cognition take place over a long
period of time following the initial insult and the innate immune system activation is a key secondary injury
mechanism that contributes to chronic neurodegeneration and loss of neurological function. In this proposal we
will investigate the respective contribution of infiltrating macrophages and activated resident microglia in
production of a neurotoxic and inflammatory milieu as well as direct interactions with neuronal synapses
following TBI in an aging animal. Preliminary data for this proposal has found that TBI causes an exacerbated
and prolonged CCR2+ macrophage infiltration in the aging brain. The increased recruitment of peripherally
derived monocytes significantly augments TBI-induced neuroinflammatory sequelae and is paralleled by an
increased expression of the superoxide-generating enzyme NOX2 which may potentiate injury-induced
cognitive dysfunction observed in old animals. All together these findings demonstrate that, in the aging brain,
peripherally derived macrophages have a distinct contribution to the TBI-related inflammatory response.
Based upon these observations we hypothesize that the robust infiltration of peripherally derived macrophages
and the consequent inflammatory response is responsible for exacerbated loss of cognitive functions by
decreasing dendritic spine density. In this proposal, we will identify the temporal relationships between
macrophage infiltration/microglia activation and inflammatory profiles in an aging brain after injury.
Furthermore, we will identify mechanistic links between macrophage infiltration and altered dendritic spine
morphology. We will determine if TBI-induced cognitive deficits are a direct result of macrophage induced ROS
production and/or inappropriate synaptic pruning. Finally, we will investigate if blockade of macrophage
infiltration can mitigate injury-induced neurotoxicity thereby alleviating cognitive deficits. Findings from this
work will advance mechanistic understanding of secondary mechanisms associated with TBI and test two
pharmacological agents (already in clinical trials) for treatment of TBI-induced cognitive deficits in an aging
animal.

## Key facts

- **NIH application ID:** 9924452
- **Project number:** 5R01AG056770-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Susanna Rosi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,300
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924452

## Citation

> US National Institutes of Health, RePORTER application 9924452, Aging exacerbates trauma-induced immune pathways and neuronal dysfunction (5R01AG056770-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9924452. Licensed CC0.

---

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