Transient Activation of Developmental Cytoskeletal Remodeling Programs After Traumatic Brain Injury: A Multiple-Reactivation Model of Neurodegeneration.

Background Traumatic brain injury (TBI) may transiently reactivate developmental cytoskeletal programs required for neural remodeling and repair. We hypothesized that, unlike the persistent embryonic pathway reactivation proposed in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), TBI produces transient reactivation followed by suppression during recovery. Methods Human transcriptomic datasets were analyzed to characterize Arp2/3-mediated cytoskeletal remodeling after TBI. Single-nucleus RNA sequencing was used to assess cell-type-specific expression, and longitudinal peripheral blood transcriptomic data were analyzed at day 1 (D1), day 7 (D7), and 6 months (M6). Arp2/3 pathway scores were evaluated using differential-expression, mixed-effects, and within-subject analyses. Results Acute TBI showed directionally increased neuronal Arp2/3 expression. Longitudinal analysis demonstrated strong temporal variation in Arp2/3 activity (p = 2.77×10⁻⁷ in complete cases). Relative to D1, pathway activity declined at D7 (estimate -0.753, p = 0.0001) and M6 (-1.009, p < 0.0001). All 12 subjects with complete longitudinal measurements had lower M6 than D1 scores. Conclusions Acute human TBI brain tissue showed activation of Arp2/3-mediated cytoskeletal remodeling, while an independent longitudinal peripheral-blood cohort showed rapid attenuation and longer-term suppression of Arp2/3 pathway activity after injury. Together, these findings are consistent with, but do not establish, a transient reactivation-resolution model.