TBI-induced adenosinergic dysregulation causes cognitive impairment and accelerates Alzheimer's disease pathology

项目摘要 流行病学研究表明，创伤性脑损伤（TBI）是发生脑损伤的重要危险因素。 阿尔茨海默病（AD），一种导致痴呆并最终， 死亡这两种情况之间的机械联系还没有得到很好的理解。此外，没有 FDA批准的广泛有效的认知障碍治疗方法，暴露了现有的大量未满足的医疗需求。 需要的继发性损伤的主要机制-氧化应激和神经炎症-不仅被认为 在TBI后，神经退行性变，但也是AD脑中发现的病理学的关键组成部分。的 文献还表明，TBI诱导tau蛋白过度磷酸化和淀粉样蛋白的聚集，神经毒性， 被认为是引发和传播AD的实体。我们所缺少的是这两者之间的潜在联系 流程.我们实验室的初步数据表明，野生型TBI后发生腺苷能失调， 小鼠，由于外核苷酸酶和腺苷激酶（ADK）的表达改变， 腺苷能张力的调节剂。腺苷能轴靶向已经过实验测试，用于认知 损伤后TBI和转基因AD小鼠，但受体特异性和心血管副作用 阻止了这些方法成为人类可行的治疗方法。我们的初步数据证明 靶向腺苷亚型3受体（A3 AR），具有> 10，000倍的受体特异性， 在野生型小鼠中TBI后的损伤，并在AD的加速老化模型中逆转它， 副作用.我认为，创伤性脑损伤诱导快速的腺苷能失调，加速病理变化 导致AD，并且在A3 AR处补充腺苷信号传导可以防止加速， 随后的认知障碍。我的建议的目标1将测试假设，TBI加速 通过在未受损的年轻小鼠中诱导TBI， 与未受伤的小鼠相比，小鼠和认知障碍发作的时间。目标2将测试 假设用高度特异性激动剂靶向A3 AR足以防止加速和认知障碍， 通过在小鼠中诱导TBI并用特异性A3 AR激动剂或其媒介物治疗来减轻损伤。组织将 在两个目标中进行生化和组织学分析。A3 AR激动剂目前正作为抗癌药物进行临床试验。 和抗炎剂。拟议研究的成功完成可能会增加另一项临床研究 A3 AR激动剂的适应症，为TBI和TBI的认知障碍治疗提供了突破， AD患者。这一项目经过仔细考虑，已纳入一项全面的研究金培训 该计划包括最先进的技术培训，多样化的指导，科学和临床职业生涯 发展职责，并有充分的机会展示我的发现。所有必要的资源， 在圣刘易斯大学的环境中，项目的完成和奖学金培训是丰富的。

Project Summary Epidemiological studies have revealed traumatic brain injury (TBI) as an important risk factor for development of Alzheimer’s disease (AD), a progressive neurodegenerative disease which results in dementia and ultimately, death. The mechanistic links between the two conditions are not well understood. Furthermore, there are no widely effective FDA approved treatments for cognitive impairment, exposing an existing large unmet medical need. Not only are major mechanisms of secondary injury—oxidative stress and neuroinflammation—thought to contribute to neurodegeneration after TBI, but are key components of pathology found in AD brains as well. The literature also suggests that TBI induces tau hyperphosphorylation and aggregation of amyloid-, neurotoxic entities thought to initiate and propagate AD. What has been missing is an underlying link between these processes. Preliminary data from our lab indicate that adenosinergic dysregulation occurs after TBI in wild type mice, resulting from altered expression of ectonucleotidase and adenosine kinase (ADK) which are key regulators of adenosinergic tone. Adenosinergic axis targeting has been tested experimentally for cognitive impairment after TBI and in transgenic AD mice, but receptor specificity and cardiovascular side effects have prevented these approaches from becoming viable treatments in humans. Our preliminary data provide evidence that targeting the adenosine subtype 3 receptor (A3AR) with >10,000 fold receptor specificity prevents cognitive impairment after TBI in wild type mice and reverses it in an accelerated aging model of AD without noticeable side effects. I propose that TBI induces rapid adenosinergic dysregulation that accelerates pathological changes which lead to AD, and that supplementing adenosine signaling at the A3AR prevents the acceleration and subsequent cognitive impairment. Aim 1 of my proposal will test the hypothesis that TBI accelerates the progression of the AD phenotype in a non-transgenic mouse model of AD by inducing TBI in young, unimpaired mice and timing the onset to cognitive impairment compared to that in uninjured mice. Aim 2 will test the hypothesis that targeting the A3AR with a highly specific agonist is sufficient to prevent acceleration and cognitive impairment by inducing TBI in mice and treating with a specific A3AR agonist or its vehicle. Tissues will be analyzed biochemically and histologically in both Aims. A3AR agonists are currently in clinical trials as anti-cancer and anti-inflammatory agents. The successful completion of the proposed studies could add another clinical indication for A3AR agonists, providing a break-through in the treatment of cognitive impairment for both TBI and AD patients. This project has been carefully considered and integrated into a comprehensive fellowship training plan which includes state of the art technical training, diverse mentorship, scientific and clinical career development duties, and ample opportunities to present my findings. All the essential resources required for completion of the project and fellowship training are abundant in Saint Louis University’s environment.