Microtubule and cytoskeletal destabilization gene expression in the brain vasculature after experimental diffuse traumatic brain injury: Implications for neurodegenerative disease later in life.

Neurodegenerative disease risk following traumatic brain injury (TBI) has been associated with vascular abnormalities and brain inflammation. However, the extent to which diffuse TBI with at least one persistent neurological deficit contributes to chronic neurodegeneration is not well understood. In this study, we investigated the impact of experimental diffuse TBI on the cerebral vasculature in the CA1 region of the hippocampus, which is vulnerable to multiple cognitive-associated neurodegenerative diseases. At 6-months post-injury, a timepoint with known cognitive impairment, we employed laser capture microdissection (LCM) to isolate parenchymal blood vessels from the CA1 subregion of the hippocampus in Sprague-Dawley rats subjected to either sham or midline fluid percussion injury. LCM vessels were processed for RNA sequencing and differentially expressed gene (DEG) analyses (DESeq2) were performed, followed by pathway enrichment analysis using genes with a log2FC > 0 and p-value < 0.05. A subset of differentially expressed genes (9%) were associated with microtubule/cytoskeletal organization, including the PLEC gene (encoding plectin) (Log2FC=+9.5, p < 0.0001), a cytoskeletal protein that maintains tissue integrity and whose overexpression has recently been identified as a risk factor for Alzheimer's disease (AD). Pathway analyses showed the most upregulated and downregulated biological pathways were involved in neurodegeneration-multiple-diseases (Gene count 11, p-adjusted < 0.01) and AD (Gene count 8, p-adjusted < 0.04). Understanding the complex interplay between TBI, the cerebral vasculature, and neurodegeneration risk is critical for prognosis and interventions that mitigate the long-term effects of brain injury and improve outcomes for patients.