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.

摘要 阿尔茨海默病(AD)是导致痴呆症的最常见原因之一，全世界有3500万人受到影响。它 其特征是认知功能丧失，形成淀粉样蛋白-β(APP-Aβ)沉积或斑块，以及 细胞内微管结合蛋白tau的积聚导致大量的神经纤维 缠结(NFT)。AD还表现为细胞信号调节失调，胰岛素信号障碍，慢性 炎症、突触丢失、细胞代谢紊乱和氧化应激。有越来越多的证据表明 AD和肠道(结肠)微生物群之间的重要联系，在那里细菌进行新陈代谢 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引起连锁反应。 在宿主的生理过程中影响骨骼新陈代谢等领域。例如，骨钙素(OC)-a 已知的骨特异性蛋白影响多种生理过程，如能量消耗、葡萄糖 动态平衡和男性生育能力-跨越血脑屏障，在那里它与脑干的神经元结合， 中脑和海马体，并影响几种神经递质的合成。重要的是，不同 OC的功能受羧化水平的调节，而OC的羧化水平受维生素的调节 钾来源于食物和肠道微生物群。据报道，低羧化形式的OC在葡萄糖中是活跃的 小鼠的新陈代谢。糖代谢改变和氧化应激导致晚期糖基化的形成 最终产物(AGEs)，与AD和糖尿病相关的骨骼脆性的发病机制有关。因此， 这个项目的总体目标是研究大脑、骨骼健康和微生物群之间的相互作用。 通过确定AD进展过程中骨骼健康和微生物群的变化来确定AD的背景(特异性 目标1)，并通过建立因果关系来研究这种变化的机制基础 微生物种群的变化(与维生素K的产生有关)，未羧化的OC水平，或 将两者结合起来，确定它们对阿尔茨海默病进展和骨骼健康的影响(具体目标2)。我们的 这些发现将建立骨-脑-肠道相互作用的机制基础，为 AD的生理学，为诊断和/或改变AD的生物标志物和治疗发现开辟了新的途径 阿尔茨海默病和/或合并症的进展。