TBI引起tau蛋白病变在工作记忆环路传播导致认知障碍及抑制A2AR的保护作用机制研究

Traumatic brain injury (TBI) may induce neurological dysfunction especially cognitive impairment during convalescence. Hyperphosphorylation of tau and propagation of tau pathology is closely associated with cognitive dysfunction. Widely spread of hyperphosphorylated tau is also observed in TBI patients' brains. But the mechanisms why it occurs earlier and develops much faster than AD and other neural degenerative diseases are still mysterious. Adenosine A2A receptors (A2ARs) are highly activated after TBI. In our previous study, tau phosphorylation related pathologies and working memory impairment were also obviously alleviated by A2AR inactivation. We suppose activation of A2AR promotes phospho-tau to propagate from hippocampus to prefrontal cortex and causes cognitive dysfunction. We will study the underlying cellular and molecular mechanisms that inhibition of tau propagation within brain by inactivation of A2AR will alleviate working memory impairment, through optogenetical technology and brain region specific A2AR knockout mice. Our study will provide an important experimental help to the understanding of how cognitive dysfunction happened and to the early apotropaic strategies of the cognitive dysfunction after TBI.

创伤性脑损伤（TBI）伤后出现以认知功能障碍为主要特征的神经功能异常是一个严重影响伤后健康的病症。已知tau蛋白磷酸化及相关病变脑内传播与认知功能障碍有关。TBI后脑内也存在大量过度磷酸化tau蛋白，但它比AD等退行性变发病更早、进展更快的机制不明。我们发现TBI后腺苷A2A受体（A2AR）被大量激活，而抑制A2AR活化可减少脑内多部位过度磷酸化tau蛋白及相关病理改变，改善工作记忆，这是否是TBI后活化的A2AR通过促进磷酸化tau蛋白由海马向前额叶皮质等记忆相关环路传播使其发病和快速进展的主要原因尚不确定。本研究将在细胞及动物整体水平对此假设进行验证，探索其细胞间传播方式及分子机制，并通过光遗传学技术及组织特异性A2AR敲除小鼠证明抑制A2AR可防止tau蛋白病变和脑内传播并缓解认知障碍等异常，以加深对脑创伤后认知障碍发生机制的认识，为早期防治提供实验依据。

TBI后认知障碍患者也有磷酸化tau蛋白，并且在各脑区特别是学习记忆的相关环路出现顺序有一定规律性，而这些变化的出现和传播速度快于AD。这些是否是TBI后认知障碍早期出现的原因目前仍不清楚。我们研究发现TBI后tau蛋白磷酸化水平升高沿工作记忆环路快速传播是早期出现认知功能障碍的原因，通过在体海马脑区注射A2AR激动剂CGS21680,检测发现小鼠tau蛋白磷酸化水平在学习记忆重要脑区海马和PFC都显著增加，并且通过水迷宫、Y-maze、T-maze等多种行为学检测范式验证了小鼠A2AR过表达可以加重tau过表达导致的空间学习记忆功能下降。并进一步对A2AR导致tau磷酸化增强的机制进行机制的探索，发现A2AR-TRAX-KIF2A 相互作用是导致认知障碍快速发病、进展迅速的重要机制。该研究为以A2AR为靶点的干预方式可以为以Tau蛋白过度磷酸化相关的神经退行性疾病的治疗提供新的干预策略。