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.

抽象的创伤性脑损伤（TBI）是阿尔茨海默氏病的众所周知的危险因素。没有一对一的关系，TBI将导致阿尔茨海默氏病的发展。缺乏直接连接建议选择性脆弱性。有问题的是，当一个人患有温和的TBI时，不可能知道是否是否他们将康复而不会影响他们的大脑健康，或者如果他们现在增加了他们的脆弱性发展阿尔茨海默氏病。可以做什么？一种方法是不久的将治疗进行广泛的治疗受伤后。由于这种方法需要治疗一些不会从TBI中恢复过的人干预，利益风险比必须很高。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在老年人中轻度TBI后使用的安全治疗人口减少发展阿尔茨海默氏病的机会。目前尚未获得FDA批准轻度TBI后使用的药物可减少继发性损伤机制。我们相信，不在轻度TBI是一个错过的机会，但是治疗需要安全。我们的初步证据表明 TBI导致能量代谢缺陷和神经炎症增加，这两者都受到了加剧先前存在的蛋白质病，例如淀粉样蛋白β。为了针对这些机制，我们已经确定了β- 羟基丁酸（BHB； 3-羟基丁酸）作为安全的多模式干预。 BHB是一个酮体，它肝脏以低级别的水平连续产生，但在禁食期间可以上升到1mm以上，卡路里限制，长时间运动或生酮饮食。临床上，BHB可以安全地口服，BHB 迅速越过血脑屏障，在饥饿的情况下，酮可以提供多达70％的大脑的能量。 BHB是一种替代生物燃料，可以绕过电子传输系统中的阻塞由淀粉样蛋白β和TBI引起，可降低线粒体生物能。 BHB也已显示通过炎症依赖性机制抑制炎症，并通过结合最近的去畸形 GPCR称为HCA2。我们将检验中心假设，即BHB将有效降低功能通过充满活力和神经炎症的轻度TBI，在APP/PS1 KI小鼠中看到的缺陷依赖机制，三个特定目标（SA）。 SA1：BHB对线粒体的剂量依赖性作用 TBI后的功能和神经炎症。 SA2：定义HCA2的免疫调节特性受体，通过烟酸的剂量依赖性作用，一种高亲和力HCA2激动剂。 SA3：定义通过丧失功能实验，通过HCA2受体进行免疫调节特性BHB。我们的工作试图解决与老年大脑脆弱性增加相关的机制，从而使其远离从轻度TBI中恢复。我们还将将BHB/HCA2轴的治疗潜力定义为TBI 在患有阿尔茨海默氏病风险的人群中使用的神经保护策略。