Influence of gut on metabolism and cognition in Alzheimer's disease.

肠道对阿尔茨海默病代谢和认知的影响。

• 批准号: 10893165
• 负责人: Abigail Lynn Hernandez
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10893165
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; American; Amyloid beta-Protein; Animal Model; Area; Bacteria; Blood; Brain; Brain-Derived Neurotrophic Factor; Butyrates; Cause of Death; Central Nervous System; Cognition; Cognitive; Data; Dementia; Diabetes Mellitus; Elderly; Energy Metabolism; Experimental Designs; Foundations; Functional disorder; Future; Generations; Geroscience; Goals; Health; Hippocampus; Homeostasis; Human; Impaired cognition; Impairment; Insulin Resistance; Intervention; Investigation; Ketone Bodies; Knowledge; Leadership; Letters; Link; Measures; Mediating; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Metagenomics; Modeling; Nature; Neurobehavioral Manifestations; Neurodegenerative Disorders; Obesity; Outcome; Pathologic; Pathology; Peripheral; Phenotype; Physiological; Population; Poverty; Prefrontal Cortex; Probiotics; Production; Quality of life; Rattus; Research; Resources; Risk; Rodent; Rodent Model; Scientific Advances and Accomplishments; Streptomycin; Supplementation; Symptoms; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thinness; Training; Transgenic Organisms; Volatile Fatty Acids; Work; aged; blood glucose regulation; brain dysfunction; brain health; brain metabolism; career development; cognitive function; cognitive process; density; dysbiosis; experimental study; functional outcomes; gastrointestinal; gastrointestinal system; gut dysbiosis; gut health; gut microbiome; gut microbiota; gut-brain axis; human data; improved; innovation; insulin sensitivity; microbiome alteration; microbiome analysis; microbiome composition; microbiota; multidisciplinary; neurogenesis; neuropathology; normal aging; novel; novel therapeutics; prevent; primary outcome; probiotic supplementation; programs; targeted treatment; tau Proteins; β-amyloid burden

PROJECT SUMMARY: Alzheimer’s disease (AD) is the most common cause of dementia and the third leading cause of death in older adults. In addition to cognitive impairment, AD is associated with neuropathology, impaired metabolic function and gut microbiome dysbiosis. However, the relationships between gut health (including the gut microbiome), metabolism and cognitive decline remains largely unknown, despite strong evidence that the gut-brain-axis is an important intermediary in neurodegenerative disease. Moreover, normal aging also influences both gut microbiome composition and peripheral metabolic health, demonstrating the importance of including geroscience as a factor. Gut dysbiosis can result in impaired insulin resistance as well as obesity, both of which increase the risk of developing AD. Therefore, the long term goal of this project is to elucidate how altered gut microbiome composition can influence cognitive outcomes in an aged rat model of AD to identify potential targets for therapeutic intervention. The overall objective is to investigate whether the gut is able to exert its influence over cognition through metabolic intermediates, as the gut microbiome directly influences metabolite production and energy homeostasis. The rationale for this project is that very few, if any, strategies directly targeting brain function have been able to prevent or delay cognitive impairment with AD to date. This line of investigation is innovative in that it suggests a peripheral target, rather than targeting the brain directly, for the alleviation of cognitive symptoms by utilizing the strong, reciprocal link between gut and brain function. Our preliminary data indicates the TgF344-AD rat model mimics the cognitive decline observed with AD, as well as the peripheral metabolic impairments and gut dysbiosis associated AD. The proposed experiments will build on these findings and test the central hypothesis that AD-associated gut dysbiosis negatively influences metabolic function, thereby impairing cognitive function through an impaired ability to properly utilize and respond to energy metabolism. Data from humans with AD, as well as our preliminary data, suggest AD-associated gut dysbiosis negatively influences butyrate production. Depletion of butyrate, the most abundant metabolite produced by the gut microbiome, is associated with many metabolic diseases including diabetes and obesity, both of which are commonly associated with AD. Supplementation of butyrate in rodent models can improve insulin sensitivity, upregulate BDNF and thereby neurogenesis and promote a lean phenotype. Butyrate improves brain health and metabolism, gut health through supporting the gastrointestinal lining quality and influences microbiome composition. These synergistic effects make systemic butyrate a therapeutic strategy, or one component of an effective strategy, with high potential to ameliorate many AD-related impairments in function. Collectively, these experiments will determine if the gut microbiome influences cognitive outcomes in aged AD-model rats through a metabolic intermediary and whether this can be ameliorated through probiotic supplementation.

项目概要： 阿尔茨海默病（AD）是痴呆症的最常见原因，也是老年人死亡的第三大原因。 成年人了除了认知障碍，AD还与神经病理学、代谢功能受损有关。 和肠道微生物群失调。然而，肠道健康（包括肠道微生物组）， 尽管有强有力的证据表明肠-脑-轴是一个神经系统，但新陈代谢和认知能力下降在很大程度上仍然是未知的。 是神经退行性疾病重要媒介。此外，正常的衰老也会影响两种肠道 微生物组组成和外周代谢健康，表明包括老年科学的重要性 作为一个因素。肠道生态失调可导致胰岛素抵抗受损以及肥胖，这两者都增加了胰岛素抵抗。 发展AD的风险。因此，该项目的长期目标是阐明如何改变肠道微生物组 本发明的组合物可以影响AD的老年大鼠模型中的认知结果，以鉴定用于治疗AD的潜在靶标。 治疗干预总体目标是研究肠道是否能够对 通过代谢中间产物的认知，因为肠道微生物组直接影响代谢产物的产生， 能量平衡这个项目的基本原理是，很少有，如果有的话，直接针对大脑的策略， 功能已经能够预防或延迟AD的认知损害。这条调查线是 创新之处在于，它提出了一个外围目标，而不是直接针对大脑，以减轻 通过利用肠道和大脑功能之间强大的相互联系来治疗认知症状。我们的初步数据 表明TgF 344-AD大鼠模型模拟了用AD观察到的认知下降，以及外周神经系统的变化。 代谢损伤和肠道生态失调相关的AD。拟议中的实验将建立在这些发现的基础上 并检验AD相关的肠道生态失调对代谢功能产生负面影响的中心假设， 从而通过损害正确利用和响应能量的能力而损害认知功能 新陈代谢.来自AD患者的数据，以及我们的初步数据，表明AD相关的肠道生态失调 负面影响丁酸盐生产。丁酸盐的消耗，丁酸盐是最丰富的代谢产物， 肠道微生物组与许多代谢疾病有关，包括糖尿病和肥胖症，两者都是 通常与AD相关。在啮齿动物模型中补充丁酸盐可以改善胰岛素敏感性， 上调BDNF，从而促进神经发生并促进瘦型。丁酸盐改善大脑健康， 通过支持胃肠道内壁质量和影响微生物组来促进新陈代谢、肠道健康 混合物.这些协同作用使全身丁酸盐成为治疗策略，或治疗的一个组成部分。 有效的策略，具有改善许多AD相关功能障碍的高潜力。总的来说，这些 实验将确定肠道微生物组是否通过以下方式影响老年AD模型大鼠的认知结果： 一种代谢中介，以及是否可以通过益生菌补充来改善。