Alzheimer's Disease, Bone Health and Microbiome

摘要 阿尔茨海默病（AD）是痴呆症最常见的原因之一，影响着全世界3500万人。它 特征在于认知功能丧失、淀粉样蛋白-β（APP-Aβ）沉积物或斑块的形成，以及 细胞内微管结合蛋白tau的积累，导致大量的神经递质 缠结（NFT）。AD还表现为细胞信号传导失调、胰岛素信号传导受损、慢性炎症、高血糖、高血糖和高血糖。 炎症、突触丧失、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）微生物组之间的重要联系，其中细菌进行代谢 反应并提供重要的营养素和维生素。对这些营养素的调节会引起涟漪反应 在宿主的生理过程中，影响到诸如骨代谢等领域。例如，骨钙素（OC）- a 已知骨特异性蛋白质影响多种生理过程，例如能量消耗、葡萄糖 体内平衡和男性生育力-穿过血脑屏障与脑干神经元结合， 中脑和海马，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; OC羧化水平受维生素C的影响。 来自食物和肠道微生物的钾。据报道，OC的低羧化形式在葡萄糖中具有活性 在小鼠体内的代谢。糖代谢改变和氧化应激导致晚期糖基化的形成 终产物（AGEs）与AD的发病机制和糖尿病相关的骨骼脆弱性有关。因此，在本发明中， 该项目的总体目标是研究大脑，骨骼健康和微生物之间的相互作用， 通过确定骨健康和微生物组随AD进展的变化来确定AD的背景（具体 目的1）并通过建立因果关系来研究这种变化的机制基础， 微生物种群的改变（与维生素K的产生有关），未羧化OC水平，或 将两种药物组合并确定其对AD进展和骨健康的影响（具体目标2）。我们 这些发现将建立骨-脑-肠相互作用的机制基础，为以下方面提供新的见解： AD的生理学，并为生物标志物和治疗发现开辟了新的途径，以诊断和/或改变AD的病理生理学。 AD和/或合并症的进展。

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.