Branched-chain amino acids as a novel biomarker and treatment for Alzheimer's disease

支链氨基酸作为新型生物标志物和治疗阿尔茨海默氏病的方法

基本信息

批准号：
10054888
负责人：
Vijay Karkal Hegde
金额：
$ 41.54万
依托单位：
TEXAS TECH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054888
关键词：
APP-PS1 Affect Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Apoptosis Applications Grants Aromatic Amino Acids Autophagocytosis Behavioral Biogenesis Biological Markers Brain Brain Pathology Branched-Chain Amino Acids Catabolism Cell physiology Cognitive deficits Data Deposition Development Diabetes Mellitus Diagnosis Diet Dietary Intervention Disease Disease Progression Dopamine Early Diagnosis Equilibrium Essential Amino Acids Exploratory/Developmental Grant FRAP1 gene Family Financial Hardship Food Funding Future Gene Expression Genes Glucose Clamp Hepatic Hippocampus (Brain)Human Impairment Individual Insulin Insulin Resistance Intake Intervention Lead Metabolic Diseases Metabolism Methods Mitochondria Molecular Mus Neocortex Neurodegenerative Disorders Neuronal Dysfunction Neurons Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Nutritional Oxidative Stress Pathogenesis Pathologic Pathology Patients Pharmaceutical Preparations Pharmacology Physiology Plasma Predisposition Proteins Quality of life Radioisotopes Reporting Role Sampling Serotonin Spinal Puncture Supplementation Symptoms Testing Time Transgenic Mice Transgenic Organisms amino acid metabolism base cognitive function cost diagnostic biomarker early screening effective therapy experimental study high risk improved in vivo insight metabolomics mortality mouse model novel novel marker predictive marker predictive modeling prevent reduce symptoms relating to nervous system response side effect synaptogenesis tau Proteins tau-1 tool

项目摘要

Project Summary Alzheimer's disease (AD) is a devastating, irreversible neurodegenerative disorder that affects over 5 million individuals in the US alone. Unfortunately, currently there is no cure or effective treatment for AD, and the lack of tools to accurately assess an individual's susceptibility and predict one's future development of AD adds another layer of complexity. Today, doctors are relying on several biomarkers to diagnose individuals with AD, but there are serious limitations with current assessment methods such as the use of radioactive isotopes, high-risk lumbar puncture, and the high cost. Clearly, more reliable, less-invasive, and patient-friendly biomarkers that can predict and/or diagnose the onset of AD is highly desired. Our preliminary data show that branched-chain amino acids (BCAAs) and their metabolites are elevated in humans with AD as well as a transgenic mouse model of AD mice compared to healthy controls. In line with these findings, BCAAs are identified as a significant composite predictor of AD in our predictive model (Figs. 1 and 2). Furthermore, a number of studies suggest that excess BCAAs can induce neural oxidative stress and apoptosis, trigger insulin resistance in the brain, and offset the balance of those neurotransmitters. Interestingly, all of these represent the pathophysiological hallmarks of AD, indicating a potential causative role of BCAAs in the pathogenesis of AD. Our pilot data show that BCAA supplementation in mature hippocampal neurons induces features of neuronal dysfunctions commonly observed in AD (Fig. 3), making BCAAs an attractive interventional target to treat AD. Experiments in the proposed study will utilize transgenic, molecular, integrative physiology, and behavioral approaches to examine 1) BCAA metabolism before and after the onset of AD-like symptoms and brain pathologies in a well-established transgenic mouse model (APP/PS1) to determine if plasma BCAAs and their metabolites can serve as a predictive and/or diagnostic biomarker for AD; and 2) whether dietary BCAA manipulation alters the progression of AD in vivo. The findings will identify novel biomarkers for prediction and detection of AD and provide new insights into the impact of BCAAs and their metabolism in the development of AD.

项目概要阿尔茨海默病 (AD) 是一种毁灭性的、不可逆转的神经退行性疾病，影响着超过 500 万人仅在美国的个人。不幸的是，目前AD还没有治愈或有效的治疗方法，而且缺乏准确评估个人易感性并预测 AD 未来发展的工具另一层复杂性。如今，医生依靠多种生物标志物来诊断 AD 患者，但目前的评估方法存在严重局限性，例如放射性同位素的使用，腰椎穿刺风险高，费用高。显然，更可靠、侵入性更小且对患者友好非常需要能够预测和/或诊断 AD 发病的生物标志物。我们的初步数据表明支链氨基酸 (BCAA) 及其代谢物在患有 AD 和 AD 小鼠的转基因小鼠模型与健康对照小鼠的比较。根据这些发现，支链氨基酸在我们的预测模型中被确定为 AD 的重要综合预测因子（图 1 和图 2）。此外，一个大量研究表明，过量的支链氨基酸会诱导神经氧化应激和细胞凋亡，触发胰岛素大脑中的阻力，并抵消这些神经递质的平衡。有趣的是，所有这些都代表 AD 的病理生理学特征，表明 BCAA 在 AD 发病机制中具有潜在的致病作用广告。我们的试验数据表明，成熟海马神经元中补充 BCAA 会诱导以下特征： AD 中常见的神经元功能障碍（图 3），使 BCAA 成为有吸引力的干预靶点治疗AD。拟议研究中的实验将利用转基因、分子、综合生理学和行为方法检查 1) AD 样症状出现前后的 BCAA 代谢和在完善的转基因小鼠模型 (APP/PS1) 中进行脑部病理学检查，以确定血浆支链氨基酸和它们的代谢物可以作为 AD 的预测和/或诊断生物标志物； 2) 是否饮食中支链氨基酸操作改变AD体内的进展。研究结果将确定用于预测和预测的新生物标志物检测 AD 并提供关于 BCAA 及其代谢在 AD 发展中的影响的新见解广告。