Donison Neil, Palik Jacqueline, Volkening Kathryn, Strong Michael J
Molecular Medicine Group, Robarts Research Institute, Western University, London, ON, Canada.
Neuroscience Graduate Program, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Mol Neurodegener. 2025 May 10;20(1):56. doi: 10.1186/s13024-025-00842-z.
Tau protein plays a critical role in the physiological functioning of the central nervous system by providing structural integrity to the cytoskeletal architecture of neurons and glia through microtubule assembly and stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated and aggregates into neurotoxic fibrillary tangles. The aggregation and cell-to-cell propagation of pathological tau leads to the progressive deterioration of the nervous system. The clinical entity of traumatic brain injury (TBI) ranges from mild to severe and can promote tau aggregation by inducing cellular mechanisms and signalling pathways that increase tau phosphorylation and aggregation. Chronic traumatic encephalopathy (CTE), which is a consequence of repetitive TBI, is a unique tauopathy characterized by pathological tau aggregates located at the depths of the sulci and surrounding blood vessels. The mechanisms leading to increased tau phosphorylation and aggregation in CTE remain to be fully defined but are likely the result of the primary and secondary injury sequelae associated with TBI. The primary injury includes physical and mechanical damage resulting from the head impact and accompanying forces that cause blood-brain barrier disruption and axonal shearing, which primes the central nervous system to be more vulnerable to the subsequent secondary injury mechanisms. A complex interplay of neuroinflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction activate kinase and cell death pathways, increasing tau phosphorylation, aggregation and neurodegeneration. In this review, we explore the most recent insights into the mechanisms of tau phosphorylation associated with TBI and propose how multiple cellular pathways converge on tau phosphorylation, which may contribute to CTE progression.
tau蛋白通过微管组装和稳定为神经元和神经胶质细胞的细胞骨架结构提供结构完整性，在中枢神经系统的生理功能中发挥关键作用。在某些病理条件下，tau蛋白异常磷酸化并聚集成神经毒性纤维缠结。病理性tau蛋白的聚集和细胞间传播导致神经系统的进行性恶化。创伤性脑损伤（TBI）的临床情况从轻度到重度不等，可通过诱导增加tau蛋白磷酸化和聚集的细胞机制和信号通路来促进tau蛋白聚集。慢性创伤性脑病（CTE）是重复性TBI的后果，是一种独特的tau蛋白病，其特征是病理性tau蛋白聚集位于脑沟深处和血管周围。导致CTE中tau蛋白磷酸化和聚集增加的机制仍有待充分明确，但可能是与TBI相关的原发性和继发性损伤后遗症的结果。原发性损伤包括头部撞击和伴随力导致的物理和机械损伤，这些力会导致血脑屏障破坏和轴突剪切，使中枢神经系统更容易受到随后的继发性损伤机制的影响。神经炎症、氧化应激、兴奋性毒性和线粒体功能障碍的复杂相互作用激活激酶和细胞死亡途径，增加tau蛋白磷酸化、聚集和神经退行性变。在这篇综述中，我们探讨了与TBI相关的tau蛋白磷酸化机制的最新见解，并提出多种细胞途径如何汇聚于tau蛋白磷酸化，这可能有助于CTE的进展。
