This study systematically summarizes the latest mechanisms of traumatic brain injury (TBI)-induced pathological tau phosphorylation and explores its potential role in chronic traumatic encephalopathy (CTE), providing theoretical support for understanding the molecular connection between TBI and CTE.
Literature Overview
The article 'Cellular and Molecular Mechanisms of Pathological Tau Phosphorylation in Traumatic Brain Injury: Implications for Chronic Traumatic Encephalopathy' published in Molecular Neurodegeneration reviews and synthesizes how traumatic brain injury induces abnormal tau phosphorylation through multiple cellular and molecular mechanisms, subsequently advancing the pathological progression of chronic traumatic encephalopathy (CTE). It emphasizes the core role of pathological tau phosphorylation and aggregation in neurodegenerative diseases post-TBI, and proposes key regulatory mechanisms involving multiple kinases (e.g., GSK3β, CDK5, ERK, JNK, and p38) and protein phosphatases (e.g., PP2A) in tau pathology. Additionally, the article discusses the application of various TBI animal models in simulating CTE pathology, providing theoretical foundations for developing disease models and therapeutic targets.
Background Knowledge
Traumatic brain injury (TBI) is a significant global contributor to neurodegenerative diseases, while chronic traumatic encephalopathy (CTE) is a tauopathy closely associated with repetitive TBI. CTE is pathologically characterized by abnormal tau accumulation in sulci and perivascular regions. Currently, CTE can only be diagnosed postmortem, with no effective biomarkers or non-invasive diagnostic methods available. At the molecular level, abnormal tau phosphorylation is a shared pathological hallmark of CTE and other tauopathies (e.g., Alzheimer's disease). Existing research confirms that multiple cellular stress pathways, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and excitotoxicity, are activated after TBI, leading to upregulation of tau phosphorylation-related kinases such as GSK3β, CDK5, ERK, JNK, and p38. Aberrant activation of these kinases not only compromises the stability of microtubule-binding domains but also promotes tau transition from physiological to pathological conformations, forming neurofibrillary tangles (NFTs). Furthermore, studies indicate that downregulation of phosphatase PP2A is equally significant in TBI and CTE, further exacerbating abnormal tau phosphorylation. Although existing animal models can simulate tau pathology post-TBI, they fail to fully replicate the stereospecific distribution of tau deposits observed in CTE. Therefore, developing animal models that better reflect human CTE pathology is a current research priority. Additionally, the study highlights the potential roles of genetic mutations (e.g., MAPT) and risk factors (e.g., APOE4) in TBI-induced CTE, offering genetic explanations for individual variability and disease susceptibility. In summary, abnormal tau phosphorylation following TBI represents a core pathological mechanism in CTE progression, and elucidating these mechanisms is critical for developing early diagnostic and targeted therapeutic strategies.
Research Methods and Experiments
This study systematically analyzed the primary molecular mechanisms of TBI-induced tau phosphorylation, including kinase activation, phosphatase inactivation, oxidative stress, and neuroinflammation, through a comprehensive review of existing TBI and CTE literature. The authors further evaluated the strengths and limitations of various TBI animal models (e.g., CCI, FPI, weight drop, blast) in recapitulating tau pathology and proposed improved models (e.g., CHIMERA) for more accurate simulation of CTE pathological features post-TBI.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides theoretical foundations for developing tau-targeted therapeutic strategies by systematically summarizing molecular mechanisms linking TBI-induced phosphorylation to CTE progression. Future research should focus on functional impacts of tau phosphorylation at specific sites, dynamic changes in kinase-phosphatase regulatory networks, and improved animal models mirroring human CTE pathology. Notably, monoclonal antibody therapies targeting cis-p-tau have shown promise in animal models, opening new avenues for clinical translation.
Conclusion
This study comprehensively elucidates the cellular and molecular mechanisms of abnormal tau phosphorylation post-TBI, revealing its central role in CTE development. It identifies neuroinflammation, oxidative stress, mitochondrial dysfunction, and kinase activation as collaborative drivers of tau pathology. While no effective treatments for CTE currently exist, targeting tau phosphorylation pathways such as GSK3β, CDK5, or PP2A may offer novel therapeutic strategies. The article also emphasizes tau's physiological functional diversity and pathological toxicity transition, providing directions for future research on dynamic tau regulation. CTE diagnostic criteria and staging systems are evolving but require longitudinal studies to validate clinical correlations. Future efforts should integrate molecular imaging, fluid biomarkers, and animal models to advance early diagnosis and personalized treatment for CTE.
