Astrocytes may drive chronic traumatic encephalopathy, scoping review finds

A systematic scoping review of 40 studies argues that chronic traumatic encephalopathy, the degenerative brain disease tied to repeated head impacts, should be understood not simply as a neuronal tauopathy but as a neuroglial disorder in which astrocytes act as integral contributors to disease progression, likely in coordination with microglia. The review, published in the Chinese Neurosurgical Journal, was designed and reported according to PRISMA 2020 guidelines and searched PubMed, Embase, Web of Science, and Scopus from database inception through December 2025. Because the included studies varied so widely in design, spanning postmortem analyses, experimental models, and biomarker research, the authors performed a qualitative synthesis rather than a formal meta-analysis.

The evidence base is small but thematically coherent. The database search identified 1847 records; after removal of 529 duplicates, 1318 unique records were screened at title and abstract level, and 132 articles underwent full-text review. Ninety-two studies were excluded for reasons such as lacking astrocytic outcome measures, insufficient mechanistic data, or failure to distinguish CTE from other tauopathies. Ultimately, 40 studies met all inclusion criteria. The authors note that the limited number reflects the highly specific inclusion criteria and the underrepresentation of astrocyte-centered investigations within the broader CTE literature, not necessarily deficiencies in the existing research. Only peer-reviewed articles published in English were included, a restriction the authors acknowledge may introduce language bias.

CTE is classically defined as a neuroglial tauopathy characterized by perivascular accumulation of hyperphosphorylated tau within neurons and astrocytes, with defining lesions localized to the depths of cortical sulci. Clinically, the condition is associated with a heterogeneous constellation of cognitive, behavioral, psychiatric, and motor symptoms, most commonly gradual degeneration of memory and executive function, mood dysregulation with increased impulsivity, and depression-like symptomology. It remains a clinicopathological diagnosis, with definitive confirmation limited to postmortem neuropathological examination, a constraint that has impeded biomarker identification and the development of targeted disease-modifying therapies.

The review converged on four mechanistic domains. The first is interface-specific astrogliosis at perivascular sulcal depths. Citing histopathological work, the authors describe perivascular glial reactivity as an essential constituent of the phosphorylated tau lesion, with astrocytic processes predominating at the earliest and most anatomically restricted sites of tau accumulation, frequently at sulcal depths where biomechanical stress is greatest during repetitive head injury. A second line of evidence concerns astrocytic degeneration: the review highlights clasmatodendrosis, characterized by cytoskeletal fragmentation and impaired ionic homeostasis, which was reported to precede overt neuronal loss. This supports a model in which neuronal vulnerability in CTE arises secondarily from compromised glial integrity rather than intrinsic neuronal dysfunction.

The second domain is disruption of aquaporin-4 polarization, whose translational relevance in humans the authors flag as uncertain. The glymphatic system, an astrocyte-dependent perivascular clearance pathway critical for metabolic waste removal, relies on polarized expression of aquaporin-4 channels that enable cerebrospinal and interstitial fluid exchange. Experimental work in mouse models showed that traumatic brain injury disrupts AQP4 polarization and reduces glymphatic flux, accelerating tau aggregation in vivo, and that loss of AQP4 polarity after injury markedly diminishes metabolic waste drainage, cultivating a permissive microenvironment for progressive proteinopathy. The review is explicit that because these studies were conducted in mice, further research is needed to establish glymphatic alterations as a central mechanism of astrocyte dysfunction in humans.

Spatial patterning reinforces the biomechanical story. A neuropathological analysis identified pronounced astrogliosis at gray and white matter junctions, locations previously predicted by computational models simulating maximal shear strain during rapid acceleration–deceleration injury. Other work correlated head impact kinematics with the spatial distribution of astrocytic p-tau pathology, and glymphatic flow has been shown to concentrate preferentially along perivascular spaces susceptible to mechanical distortion, while age- and injury-related AQP4 depolarization further exacerbates clearance deficits. Together, the review argues, these findings integrate astrocytic degeneration and glymphatic failure into a unified pathogenic axis in which regionally patterned astrocytic dysfunction may precede and facilitate tau accumulation.

The third domain involves astrocytic degeneration and impaired glutamate homeostasis. Astrocytes regulate synaptic glutamate through the excitatory amino acid transporter 2, and loss or dysfunction of EAAT2 disrupts glutamate clearance, which is linked to excitotoxic neuronal injury. The review describes astrocytic EAAT2 downregulation in CTE as a potential link between repetitive head trauma and persistent synaptic dysfunction, suggesting neuronal pathology may be secondary to impaired glial support. Coordinated astrocyte and oligodendrocyte alterations in CTE further emphasize that pathogenesis extends beyond neurons to the interconnected glial network. Metabolic dysfunction may amplify vulnerability: endothelial nitric oxide synthase uncoupling was identified as a contributor to oxidative stress and p-tau accumulation within astrocytes, implicating disrupted astrocyte–vascular metabolic coupling.

The fourth domain is sustained neuroinflammation mediated through astrocyte–microglia signaling. The review recounts the A1 neurotoxic astrocyte phenotype, inducible by microglial proinflammatory cytokines including interleukin-1α, TNF-α, and complement component C1q, characterized by loss of synaptotrophic support and gain of neurotoxic functions, while noting that this dichotomy has more recently transitioned to a spectrum of astrocyte inflammatory activity. In postmortem CTE tissue, microglial activation was reported to precede and spatially predict astrocytic tau deposition, suggesting coordinated microglia–astrocyte signaling. Chronic glial activation was found to persist well beyond the initial traumatic event, pointing to a possible self-perpetuating cycle in which astrocytes act as both effectors and amplifiers of neuroinflammation. The authors caution, however, that data on astrocytic neuroinflammation are shared across many neurodegenerative disorders and are not specific to CTE.

Distinguishing CTE from other tauopathies remains central to the review’s argument. Age-related tau astrogliopathy involves subpial and periventricular astrocytic tau deposition following anatomical distributions independent of traumatic exposure, whereas astrocytic tau in CTE exhibits highly specific localization to perivascular regions at the depths of cortical sulci, a feature not observed in Alzheimer’s disease or ARTAG. The NINDS consensus diagnostic criteria formalized these distinctions by establishing perivascular p-tau aggregates in neurons and astrocytes at specific sulcal depths as disease-defining. Spatial transcriptomics further showed that CTE-associated astrocytes exhibit coordinated dysregulation of glutamate transport, inflammatory signaling, and cytoskeletal maintenance pathways, with transcriptional profiles distinct from those in Alzheimer’s disease and ARTAG, providing molecular validation that CTE astrocytic pathology represents a unique glial phenotype rather than a nonspecific response to tau accumulation. The interface between CTE and ARTAG, however, remains an area of ongoing uncertainty, since both involve tau deposition and may occur simultaneously.

On translational biomarkers, circulating GFAP emerged as a sensitive but non-specific indicator of neuroglial injury. Blood levels of GFAP and tau rise after head trauma, reflecting acute astroglial disruption and blood–brain barrier compromise and neuronal or axonal damage respectively, but such biomarkers can be elevated in a wide range of neurological insults, including acute traumatic brain injury, making CTE-specific markers difficult to identify. The review frames antemortem diagnosis of CTE as the field’s

Subject of Research: The role of astrocytes in the pathogenesis of chronic traumatic encephalopathy

Article Title: Astrocytic contributions to the pathogenesis of chronic traumatic encephalopathy: a scoping review

Article References: Kubiak, A., Hahn, K., Powers, N., Arroyo, E., Vandello, C., Martins, J., & He, L. (2026). Astrocytic contributions to the pathogenesis of chronic traumatic encephalopathy: a scoping review. Chinese Neurosurgical Journal, 12(1), Article 15. https://doi.org/10.1186/s41016-026-00434-w

Image Credits: AI Generated

DOI: 10.1186/s41016-026-00434-w

Keywords: chronic traumatic encephalopathy, astrocytes, tauopathy, repetitive head impacts, glymphatic system, aquaporin-4, GFAP biomarker, neuroinflammation, glutamate homeostasis, scoping review, postmortem diagnosis, microglia