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.