Proposed mechanisms of tau: relationships to traumatic brain injury, Alzheimer's disease, and epilepsy.
Proposed mechanisms of tau: relationships to traumatic brain injury, Alzheimer's disease, and epilepsy.
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DOI：
10.3389/fneur.2023.1287545
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发表时间：
2023
影响因子：
3.4
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中科院分区：
文献类型：
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创伤性脑损伤（TBI）、阿尔茨海默病（AD）和癫痫具有共同的损伤机制，包括神经元兴奋性毒性、级联信号传导和tau等蛋白质生物标志物的激活。尽管tau通常存在于细胞内，但在tau蛋白病中，磷酸化（p-）和超磷酸化（hp-）tau在细胞外释放，后者导致神经元稳定性降低和神经元缠结（NFT）。在特定位点的Tau切割增加了对过度磷酸化、NFT形成和最终细胞死亡的易感性。然而，tau蛋白与炎症之间的关系尚不清楚。在这篇综述中，我们提出的证据不平衡的内质网（ER）应激反应和炎症信号通路导致非典型的p-tau，hp-tau和NFT的形成。此外，我们提出tau蛋白作为TBI，AD和癫痫中神经元损伤严重程度的生物标志物。我们提出了一个假设，tau蛋白磷酸化作为癫痫发作/TBI的初始急性神经保护反应。然而，如果潜在的癫痫病理或TBI复发没有得到有效治疗，并且该途径变得慢性激活，我们提出了一个“临界点”假说，该假说确定了tau磷酸化从神经保护性到损伤性的转变。我们概述了淀粉样蛋白β（Aβ）作为“最后努力”的作用，以恢复细胞的程序性死亡信号，当失败时，将机制从损伤性转变为神经退行性。最后，我们讨论了目标沿着这些途径的治疗干预AD，TBI和癫痫。
Traumatic brain injury (TBI), Alzheimer’s disease (AD), and epilepsy share proposed mechanisms of injury, including neuronal excitotoxicity, cascade signaling, and activation of protein biomarkers such as tau. Although tau is typically present intracellularly, in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, the latter leading to decreased neuronal stability and neurofibrillary tangles (NFTs). Tau cleavage at particular sites increases susceptibility to hyper-phosphorylation, NFT formation, and eventual cell death. The relationship between tau and inflammation, however, is unknown. In this review, we present evidence for an imbalanced endoplasmic reticulum (ER) stress response and inflammatory signaling pathways resulting in atypical p-tau, hp-tau and NFT formation. Further, we propose tau as a biomarker for neuronal injury severity in TBI, AD, and epilepsy. We present a hypothesis of tau phosphorylation as an initial acute neuroprotective response to seizures/TBI. However, if the underlying seizure pathology or TBI recurrence is not effectively treated, and the pathway becomes chronically activated, we propose a “tipping point” hypothesis that identifies a transition of tau phosphorylation from neuroprotective to injurious. We outline the role of amyloid beta (Aβ) as a “last ditch effort” to revert the cell to programmed death signaling, that, when fails, transitions the mechanism from injurious to neurodegenerative. Lastly, we discuss targets along these pathways for therapeutic intervention in AD, TBI, and epilepsy.
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