Cellular responses to repetitive head impacts: microglial neuroinflammation, neuronal loss, and tau pathology in chronic traumatic encephalopathy
Date
2025
DOI
Version
OA Version
Citation
Abstract
Repetitive head impacts (RHI) sustained from contact sports, military-related activities, and interpersonal violence are the largest risk factor for the neurodegenerative disease chronic traumatic encephalopathy (CTE). Exposure to RHI induces a cascade of multicellular events including neuroinflammation and microvascular damage and can eventually result in deposition of CTE p-tau. Currently, CTE can only be diagnosed with certainty after death by identifying the pathognomonic lesion of CTE, a perivascular accumulation of hyperphosphorylated tau (p-tau) as neurofibrillary tangles and neurites at the depth of the cortical sulcus. The manner by which RHI leads to p-tau aggregation is poorly understood, and the extent and localization of p-tau deposition in early stage CTE does not explain symptoms endorsed by young individuals. In addition, the role of neurons and astrocytes in early p-tau accumulation and the progression of the CTE lesion have not been analyzed quantitatively. Here, we 1) describe the cellular distribution of p-tau across the progression of CTE from early-stage disease to high-stage, severe CTE, 2) present a case report of a 32-year-old former National Football League player with early-stage CTE and pronounced behavioral changes, and 3) characterize the early cellular cascade induced by exposure to RHI in young individuals (<51 years old). We show that p-tau predominantly accumulates in neurons in early-stage CTE and associates with years of RHI exposure, while astrocytic p-tau is associated with age. We detail the pathological features of a 32-year-old NFL player who was diagnosed with CTE stage II and discuss the relationship of p-tau pathology to his behavioral changes. We also show that RHI exposure induces microglial neuroinflammation, astroglial reactivity, and endothelial angiogenic responses and a significant loss of Layer 2/3 neurons using single nucleus RNA sequencing. Loss of layer 2/3 neurons shows a dose-response relationship with RHI exposure and is independent of p-tau deposition. These results provide robust evidence that RHI exposure induces substantial cellular alterations in advance of p-tau deposition in young individuals that may promote CTE pathogenesis and contribute to clinical symptoms. Furthermore, these data provide new starting points for the development of diagnostics and therapeutics targeting RHI-induced cellular responses and early accumulation of neuronal p-tau in CTE.
Description
2025
License
Attribution-NonCommercial-ShareAlike 4.0 International