Alzheimer's Disease, Bone Health and Microbiome

阿尔茨海默病、骨骼健康和微生物组

• 批准号: 10064449
• 负责人: Blanca Barquera
• 金额: $ 46.28万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064449
• 关键词: Advanced Glycosylation End Products; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Area; Bacteria; Bacteroides; Bifidobacterium; Binding; Binding Proteins; Biochemical; Biochemistry; Biological Markers; Biomechanics; Blood - brain barrier anatomy; Bone Density; Brain; Brain Stem; Chronic; Clostridium; Cognitive; Data; Dementia; Deposition; Development; Diabetes Mellitus; Diagnosis; Disease Progression; Energy Metabolism; Environment; Exhibits; Food; Geometry; Germ-Free; Goals; Health; Health Care Costs; Hippocampus (Brain); Human; Immunologics; Impaired cognition; Impairment; Individual; Inflammation; Infusion procedures; Intraperitoneal Injections; Lead; Link; Measures; Metabolic; Metabolic Diseases; Microtubules; Midbrain structure; Modeling; Mus; Nesting Behavior; Neurofibrillary Tangles; Neurons; Neurotransmitters; Nutrient; Osteocalcin; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Physiological Processes; Physiology; Population; Production; Property; Proteins; Quality of life; RNA; Reaction; Recombinants; Regulation; Reporting; Sampling; Serum; Signal Transduction; Structure; Synapses; Therapeutic; Time; Vitamin K; Vitamins; amyloid formation; blood glucose regulation; bone; bone health; bone loss; bone metabolism; bone quality; brain tissue; carboxylation; cognitive function; colon microbiome; comorbidity; cortical bone; dysbiosis; glucose metabolism; gut microbiome; gut microbiota; gut-brain axis; high risk; insight; insulin signaling; male fertility; microbial; microbiome; microbiome composition; mineralization; mouse model; offspring; skeletal; stool sample; substantia spongiosa; tau Proteins

Abstract Alzheimer’s disease (AD), one of the most common causes of dementia, affects 35 million people worldwide. It is characterized by loss of cognitive function, formation of amyloid-β (APP-Aβ) deposits or plaques, and accumulation of intracellular microtubule-binding protein tau which leads to an abundance of neurofibrillary tangles (NFTs). AD also presents cellular signaling dysregulation, impairment of insulin signaling, chronic inflammation, synapse loss, cellular metabolism disorders, and oxidative stress. There is increasing evidence of a significant connection between AD and the gut (colon) microbiome where the bacteria carry out metabolic reactions and provide important nutrients and vitamins. Regulation of these nutrients can cause ripple effects throughout a host’s physiology which affect areas such as bone metabolism. For example, osteocalcin (OC) – a bone specific protein known to influence diverse physiological processes such as energy expenditure, glucose homeostasis and male fertility – crosses the blood brain barrier where it binds to neurons of the brainstem, midbrain, and hippocampus, and influences the synthesis of several neurotransmitters. Importantly, different functions of OC are regulated by the level of carboxylation; and level of OC carboxylation is governed by vitamin K derived from food and gut microbiome. The undercarboxylated form of OC was reported to be active in glucose metabolism in mice. Altered glucose metabolism and oxidative stress lead to formation of advanced glycation end-products (AGEs) that are linked to both the pathogenesis of AD and diabetes related skeletal fragility. Thus, the overall goal of this project is to investigate the interactions between brain, bone health and microbiome in the context of AD by determining the alterations in bone health and microbiome with AD progression (Specific Aim 1) and to investigate the mechanistic basis of such changes by establishing cause and effect through alterations of the microbial population (associated with production of vitamin K), uncarboxylated OC levels, or a combination of two and determining their impact on AD progression and bone health (Specific Aim 2). Our findings will establish the mechanistic underpinnings of the bone-brain-gut interactions, provide new insight into physiology of AD, and open new avenues for biomarker and therapeutic discovery to diagnose and/or alter the progression of AD and/or comorbidirites.

抽象的 阿尔茨海默病 (AD) 是导致痴呆症的最常见原因之一，影响着全世界 3500 万人。 其特征是认知功能丧失、淀粉样蛋白-β (APP-Aβ) 沉积物或斑块形成，以及 细胞内微管结合蛋白 tau 的积累，导致神经原纤维的丰富 AD 还表现为细胞信号传导失调、胰岛素信号传导受损、慢性。 越来越多的证据表明，炎症、突触损失、细胞代谢紊乱和氧化应激。 AD 与肠道（结肠）微生物组之间存在重要联系，细菌在肠道微生物组中进行代谢 反应并提供重要的营养素和维生素。对这些营养素的调节可能会产生连锁反应。 贯穿宿主的生理机能，影响骨代谢等领域，例如骨钙素（OC）——一种 已知骨特异性蛋白质会影响多种生理过程，例如能量消耗、葡萄糖 体内平衡和男性生育能力——穿过血脑屏障，与脑干神经元结合， 重要的是，不同的神经递质的合成。 OC的功能受羧化水平调节；OC羧化水平受维生素控制； 据报道，OC 的羧基化形式在葡萄糖中具有活性。 小鼠体内葡萄糖代谢的改变和氧化应激导致晚期糖基化的形成。 终产物 (AGE) 与 AD 的发病机制和糖尿病相关的骨骼脆弱性有关。 该项目的总体目标是研究大脑、骨骼健康和微生物组之间的相互作用 通过确定 AD 进展过程中骨骼健康和微生物组的变化来了解 AD 的背景（具体 目标 1) 并通过建立因果关系来调查此类变化的机制基础 微生物种群的改变（与维生素 K 的产生相关）、未羧化的 OC 水平或 结合两者并确定它们对 AD 进展和骨骼健康的影响（我们的具体目标 2）。 研究结果将建立骨-脑-肠相互作用的机制基础，提供新的见解 AD 的生理学，并为诊断和/或改变 AD 的生物标志物和治疗发现开辟新途径 AD 和/或合并症的进展。