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

TBI 诱导的腺苷能失调导致认知障碍并加速阿尔茨海默病病理

• 批准号: 10660950
• 负责人: Monica N. Goodland
• 金额: $ 4.43万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10660950
• 关键词: AD transgenic mice; Acceleration; Acute; Address; Adenosine; Adenosine A3 Receptor; Adenosine Kinase; Affect; Age; Age Months; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amnesia; Amyloid; Anti-Inflammatory Agents; Athletic Injuries; Attenuated; Behavioral; Biochemical; Brain; Brain Injuries; Cardiovascular system; Central Nervous System; Cessation of life; Chronic; Clinical; Clinical Trials; Cognitive deficits; Confusion; Data; Dementia; Development; Drops; Emergency department visit; Environment; FDA approved; Fellowship; Genes; Goals; Harvest; Head; Hippocampus; Histologic; Hospitalization; Human; Impaired cognition; Impairment; Incidence; Individual; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukins; Knowledge; Learning; Life; Link; Literature; Measures; Mediating; Mediator; Medical; Memory impairment; Mentorship; Metabolism; Military Personnel; Mitochondria; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Patients; Persons; Prefrontal Cortex; Procedures; Process; Production; Quality of life; Receptor Signaling; Resources; Risk; Risk Factors; Safety; Signal Transduction; Specificity; Speech; Symptoms; Testing; Time; Tissues; Training; Traumatic Brain Injury; United States; Universities; Weight; Wild Type Mouse; age related; anti-cancer; automobile accident; cancer therapy; career development; cognitive change; cognitive function; contact sports; dementia risk; disease phenotype; ecto-nucleotidase; epidemiology study; experimental study; extracellular; falls; hyperphosphorylated tau; improved; insight; marenostrin; mild traumatic brain injury; mitochondrial dysfunction; mouse model; neuroinflammation; neurotoxic; novel; novel therapeutics; oxidative damage; prevent; receptor; senescence; side effect; tau-1

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.

项目摘要 流行病学研究表明，创伤性脑损伤(TBI)是脑损伤发生的重要危险因素。 阿尔茨海默病(AD)是一种进行性神经退行性疾病，会导致痴呆，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批准了广泛有效的认知障碍治疗方法，暴露了现有的大型未获满足的医学 需要。继发性损伤的主要机制-氧化应激和神经炎症-不仅被认为是 有助于脑外伤后的神经退行性变，但也是AD大脑中发现的病理的关键组成部分。这个 文献还表明，颅脑损伤可诱导tau过度磷酸化和淀粉样蛋白聚集，具有神经毒性 被认为发起和传播AD的实体。一直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，野生型颅脑损伤后发生了腺苷能失调。 小鼠，由关键的ECT和ADK的表达变化引起 腺苷能张力的调节剂。腺苷能轴靶向已被实验测试为认知功能 颅脑损伤后和转基因AD小鼠的损害，但受体特异性和心血管副作用 阻止了这些方法在人类身上成为可行的治疗方法。我们的初步数据提供了证据 以10,000倍受体特异性的腺苷亚型3受体(A3AR)为靶标可阻止认知 颅脑损伤后野生型小鼠的损伤及无明显阿尔茨海默病加速衰老模型的逆转 副作用。我认为，脑外伤会导致快速的腺苷能失调，从而加速病变。 这会导致AD，在A3AR补充腺苷信号可以防止加速和 随后的认知障碍。我提案的目标1将检验以下假设：TBI加速了 非转基因AD小鼠模型中未受损伤的幼鼠脑损伤后AD表型的研究进展 并与未受伤的小鼠相比，将认知障碍的发病时间定为小鼠。目标2将测试 假设使用高度特异的激动剂靶向A3AR足以防止加速和认知 通过在小鼠中诱发脑损伤并用特定的A3AR激动剂或其载体治疗而造成的损伤。纸巾将成为 对这两个目标进行了生化和组织学分析。A3AR激动剂目前正在作为抗癌药物进行临床试验 和抗炎药。拟议研究的成功完成可能会增加另一个临床 A3AR激动剂的适应症，为脑外伤和脑外伤认知障碍的治疗提供了突破 AD患者。该项目经过仔细考虑，并纳入了一项全面的团契培训。 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的计划 发展职责，以及充分的机会来展示我的发现。所需的所有必要资源 在圣路易斯大学的环境中，项目的完成和奖学金培训非常丰富。