Translational Approaches to Mitigate Enhanced Alzheimer’s Disease Risk Following a Mild TBI

减轻轻度 TBI 后阿尔茨海默病风险增加的转化方法

基本信息

批准号：
10090757
负责人：
ADAM D BACHSTETTER
金额：
$ 114.75万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090757
关键词：
APP-PS1 Acids Address Adult Affinity Age Agonist Agreement Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Assisted Living Facilities Binding Bioenergetics Blood - brain barrier anatomy Brain Bypass Caloric Restriction Chronic Clinical Closed head injuries Cognitive Cognitive deficits Complex Data Dementia Development Disease Dose Elderly Electron Transport Energy Metabolism Environmental Risk Factor Epidemiology Exercise Experimental Designs Exposure to FDA approved Family member Fasting G-Protein-Coupled Receptors Goals Head Implant Incidence Independent Living Individual Inflammasome Inflammation Injury Interleukin-1 beta Intervention Ketone Bodies Ketones Knock-in Mouse Knockout Mice Life Liver Measures Microglia Mitochondria Mus Neurodegenerative Disorders Neurologic Nicotinic Acids Odds Ratio Oral Pathologic Pathology Persons Pharmaceutical Preparations Population Populations at Risk Positron-Emission Tomography Property Pump Radiology Specialty Receptor Activation Recovery Reporting Risk Risk Factors Societies Starvation System TBI treatment Testing Therapeutic Time Traumatic Brain Injury Work beta amyloid pathology beta-Hydroxybutyrate brain health design efficacious intervention experience experimental study falls human old age (65+)immunoregulation ketogenic diet loss of function loved ones medical attention member mild traumatic brain injury mitochondrial dysfunction modifiable risk mouse model multi-component intervention neurodegenerative dementia neuroinflammation pre-clinical prevent receptor subcutaneous translational approach young adult β-amyloid burden

项目摘要

ABSTRACT A traumatic brain injury (TBI) is a well-known risk factor for Alzheimer's disease. There is not a one-to-one relationship, where a TBI will lead to the development of Alzheimer's disease. The lack of a direct connection suggests a selective vulnerability. Problematically, when a person has a mild TBI, it is not possible to know if they will recover without an impact on their brain health or if they have now increased their vulnerability to developing Alzheimer's disease. What can be done? One approach is a broad administration of therapy shortly after the injury. Since this approach requires treating some people who would recover from the TBI without intervention, the benefit-to-risk ratio must be very high. That is, you do not want to cause harm by giving an unneeded drug. Our long-term goal is to identify safe treatments to be used after a mild TBI in an older adult population to lessen the chance of developing Alzheimer's disease. There are currently no FDA approved drugs to be used after a mild TBI to reduce secondary injury mechanisms. We believe that not treating after a mild TBI is a missed opportunity, but the treatment needs to be safe. Our preliminary evidence shows that a TBI causes deficits in energy metabolism and increased neuroinflammation, both of which are exacerbated by preexisting proteinopathies, such as amyloid-beta. To target these mechanisms, we have identified Beta- hydroxybutyrate (BHB; 3-hydroxybutyric acid) as a safe multimodal intervention. BHB is a ketone body, which is continuously produced by the liver at low levels but can rise above 1mM during periods of fasting, calorie restriction, prolonged exercise, or by the ketogenic diet. Clinically, BHB is safe to be administered orally, BHB rapidly crosses the blood-brain-barrier, and in cases of starvation, ketones can provide as much as 70% of the brain's energy. BHB is an alternative biofuel, that can bypass blockages in the electron transport system caused by amyloid-beta, and TBI, which decrease mitochondrial bioenergetics. BHB has also been shown to suppress inflammation via an inflammasome-dependent mechanism and by binding to a recently deorphanized GPCR called HCA2. We will test the central hypothesis that BHB will be effective at reducing functional deficits seen in APP/PS1 KI mice following a mild TBI through both energetic and neuroinflammatory dependent mechanisms, in three specific aims (SA). SA1: Dose-dependent effects of BHB on mitochondrial function and neuroinflammation after TBI. SA2: Define the immunomodulatory properties of the HCA2 receptor, via dose-dependent effects of niacin, a high-affinity HCA2 agonist. SA3: Define the immunomodulatory properties BHB through the HCA2 receptor through loss of function experiment. Our work seeks to address the mechanisms associated with the increased fragility of the older brain which keeps it from recovering from a mild TBI. We also will define the therapeutic potential of the BHB/HCA2 axis as a post-TBI neuroprotective strategy for use in a population at risk for Alzheimer's disease.

抽象的众所周知，创伤性脑损伤 (TBI) 是阿尔茨海默病的危险因素。不存在一对一的关系，其中 TBI 将导致阿尔茨海默病的发展。缺乏直接联系表明存在选择性脆弱性。问题是，当一个人患有轻度 TBI 时，不可能知道是否他们会康复，不会影响他们的大脑健康，或者如果他们现在更容易受到影响患阿尔茨海默病。可以做什么？一种方法是短期内进行广泛的治疗受伤后。由于这种方法需要治疗一些无需治疗就能从 TBI 中恢复的人干预，收益风险比一定非常高。也就是说，您不想通过给予不需要的药物。我们的长期目标是确定老年人轻度 TBI 后使用的安全治疗方法人口减少患阿尔茨海默病的机会。目前尚无 FDA 批准轻度 TBI 后使用的药物可减少继发性损伤机制。我们认为，如果不进行治疗，轻度 TBI 是一个错失的机会，但治疗需要安全。我们的初步证据表明 TBI 会导致能量代谢缺陷和神经炎症增加，这两种情况都会因以下因素而加剧：先前存在的蛋白质病，例如β淀粉样蛋白。为了针对这些机制，我们已经确定了 Beta- 羟基丁酸（BHB；3-羟基丁酸）作为一种安全的多模式干预措施。 BHB是酮体，由肝脏持续以低水平产生，但在禁食、卡路里摄入期间可升至 1mM 以上限制、长时间运动或生酮饮食。临床上，BHB口服给药是安全的，BHB 酮能迅速穿过血脑屏障，在饥饿的情况下，酮可以提供高达 70% 的能量。大脑的能量。 BHB 是一种替代生物燃料，可以绕过电子传输系统中的堵塞由β淀粉样蛋白和TBI引起，会降低线粒体生物能。 BHB 还被证明可以通过炎症小体依赖性机制并通过与最近脱孤儿结合来抑制炎症 GPCR 称为 HCA2。我们将测试 BHB 将有效减少功能性的中心假设 APP/PS1 KI 小鼠在轻度 TBI 后通过能量和神经炎症表现出缺陷依赖机制，在三个具体目标（SA）中。 SA1：BHB 对线粒体的剂量依赖性影响 TBI 后的功能和神经炎症。 SA2：定义 HCA2 的免疫调节特性受体，通过烟酸（一种高亲和力 HCA2 激动剂）的剂量依赖性作用。 SA3：定义免疫调节特性 BHB 通过 HCA2 受体丧失功能实验。我们的工作寻求解决与老年大脑脆弱性增加相关的机制，该脆弱性使其免受影响从轻度 TBI 中恢复。我们还将 BHB/HCA2 轴定义为 TBI 后的治疗潜力用于有阿尔茨海默病风险的人群的神经保护策略。