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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.

项目总结