# Immune-specific EphA4 influence meningeal amyloid accumulation following TBI

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $380,127

## Abstract

ABSTRACT
Neuroinflammation is a critical component of trauma-induced secondary injury that is capable of mediating the
production of Aβ plaques commonly seen in dementia-like neurological sequela. The epidemiological link
between TBI and dementia is well supported with TBI patients having an increased lifelong risk of developing
dementia. One of the earliest observable pathologies in the AD brain is a global reduction in CBF, and our novel
preliminary findings suggest that reduced CBF is associated with substantial vascular Aβ plaque accumulation
in the pial layer of the cranial meninges of J20 (PDGF-APPSw, Ind) mice that we discovered is uniquely restricted
to the pial arterial vascular network. Recent scRNAseq studies show inflammatory gene alterations in meningeal
macrophages following mild TBI (mTBI). It remains unknown whether chronic meningeal inflammation following
brain injury in aged individuals can contribute to neurodegenerative sequela. The parent grant has established
that the EphA4/Tie2 axis regulates the inflammatory state of monocyte/macrophages and that BMC chimeric
loss of EphA4 reduces TBI deficits. The objective of this supplement is to characterize the mechanism(s)
underlying chronic meningeal inflammation and establish whether Aβ plaque deposition is accelerated in J20
mice following mTBI. We will further establish these longitudinal effects in a sex-specific manner using GFP BMC
chimeric approaches. We hypothesize that EphA4 supports a chronic pro-inflammatory environment in the
meninges leading to vascular Aβ plaque accumulation and cognitive deficits in J20 mice that are accelerated
following mTBI. This study will highlight the pathophysiological relevance of the novel Aβ plaque meningeal
phenotype and establish whether peripheral immune cells are involved in this process.

## Key facts

- **NIH application ID:** 10939660
- **Project number:** 3R01NS121103-04S1
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Michelle Lee Theus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,127
- **Award type:** 3
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939660

## Citation

> US National Institutes of Health, RePORTER application 10939660, Immune-specific EphA4 influence meningeal amyloid accumulation following TBI (3R01NS121103-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10939660. Licensed CC0.

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