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

基本信息

批准号：
10464395
负责人：
Monica N. Goodland
金额：
$ 3.5万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10464395
关键词：
AD transgenic mice Acceleration Acute Address Adenosine Adenosine A3 Receptor Adenosine Kinase Affect Age Age-Months Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amnesia Amyloid Anti-Inflammatory Agents Athletic Injuries Attenuated Behavioral Biochemical Brain Brain Injuries Cardiovascular system Cessation of life Chronic Clinical Clinical Trials Cognitive deficits Confusion Data Dementia Development Drops Emergency department visit Environment FDA approved Fellowship Goals Harvest Head Hippocampus (Brain)Histologic Hospitalization Human Impaired cognition Impairment Incidence Individual Inflammasome Inflammation Inflammation Mediators Inflammatory Injury Interleukins Knowledge Lead Learning Life Link Literature Measures Mediating Mediator of activation protein Medical Memory impairment Mentorship Metabolism Military Personnel Mitochondria Mus Nerve Degeneration Neuraxis 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 Saints 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 development cognitive function contact sports dementia risk disease phenotype 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 Proteins tau phosphorylation tau-1

项目摘要

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）是发展的重要危险因素阿尔茨海默氏病（AD），一种进行性神经退行性疾病，导致痴呆症，最终导致死亡。两种条件之间的机械联系尚不清楚。此外，没有 FDA批准的认知障碍疗法广泛有效，暴露了现有的大型未满足医疗需要。不仅是继发性损伤的主要机制 - 氧化应激和神经炎症 - 在TBI之后有助于神经变性，但也是AD大脑中病理学的关键组成部分。这文献还表明，TBI诱导淀粉样蛋白，神经毒性的TAU高磷酸化和聚集被认为启动和传播广告的实体。缺少的是这些之间的基本联系过程。来自我们实验室的初步数据表明腺苷能功能失调发生在野生型TBI之后小鼠，是由于依顿核苷酸酶和腺苷激酶（ADK）的表达改变而产生的，这是关键腺苷能基调的调节剂。腺苷能轴靶向已通过实验测试 TBI和转基因AD小鼠后的损伤，但接收器的特异性和心血管副作用具有阻止了这些方法成为人类的可行疗法。我们的初步数据提供了证据靶向具有> 10,000倍受体特异性的腺苷亚型3受体（A3AR）可阻止认知 TBI在野生型小鼠中的损伤，并以AD的加速衰老模型将其逆转而无需明显副作用。我建议TBI会影响快速的腺苷能失调，从而加速病理变化这导致AD，并在A3AR上补充腺苷信号传导可防止加速和我的提案的目标1将检验以下假设，即TBI加速了 Young，Unipaired TBI在非转基因小鼠AD的非转基因小鼠模型中的AD表型的进展与未受伤的小鼠相比，小鼠和时间对认知障碍的发作时间。 AIM 2将测试假设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导TBI并用特定的A3AR激动剂或其车辆治疗损害。组织会在两个目标中对生化和组织学进行了分析。 A3AR激动剂目前正在临床试验中作为抗癌者和抗炎剂。拟议研究的成功完成可能会增加另一个临床 A3AR激动剂的迹象，在治疗TBI和TBI的认知障碍方面提供了突破性广告患者。该项目已经过仔细考虑，并将其整合到全面的奖学金培训中计划包括最先进的技术培训，不同的精神训练，科学和临床职业发展职责，并有足够的机会提出我的发现。所有必需的基本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。