Microbiota-targeted approaches to resolve dysbiosis-induced AD neuropathology following brain injury.

以微生物群为目标的方法来解决脑损伤后生态失调引起的 AD 神经病理学问题。

• 批准号: 10910348
• 负责人: Sonia Villapol
• 金额: $ 64.26万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10910348
• 关键词: APP-PS1; Ablation; Acceleration; Acute; Affect; Aftercare; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Antibiotics; Anxiety; Bacteria; Behavior; Brain; Brain Injuries; Chronic; Cognitive deficits; Communication; Computer Analysis; DNA sequencing; Data; Dementia; Deposition; Disease Progression; Elderly; Encephalitis; Engraftment; Environmental Risk Factor; Event; Flow Cytometry; Foundations; Functional disorder; Gastrointestinal Physiology; Germ-Free; Hip region structure; Hospitals; Immune; Immune system; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Intervention; Lactobacillus; Mediating; Mental Depression; Metabolic; Microglia; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurological outcome; Neuromodulator; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Persons; Phase; Play; Probiotics; Process; Production; Proteins; Recovery; Rehabilitation therapy; Research Proposals; Role; Severities; Signal Transduction; Testing; Tg2576; Therapeutic; Traumatic Brain Injury; Traumatic Brain Injury recovery; Traumatic CNS injury; Vulnerable Populations; abeta accumulation; bacteriome; behavior test; bone; cognitive function; design; dysbiosis; experimental study; extracellular; fall risk; falls; fecal transplantation; global health; gut bacteria; gut microbiome; gut microbiota; gut-brain axis; high risk; immune activation; improved; injured; metabolomics; metaproteomics; microbial; microbiome; microbiome composition; microbiota; microbiota-gut-brain axis; motor deficit; mouse model; multidisciplinary; nervous system disorder; neuroinflammation; neuropathology; next generation; patient population; preservation; response; restoration; tau Proteins; tau aggregation; tau-1

PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in cognitive decline. The neuroinflammatory events that are associated with the pathology of AD exacerbate neurodegeneration. Elderly people with dementia or AD have a higher risk of falling because their cognitive function is affected. They lose their orientation and are very prone to breaking their hips, other bones, or even more severe falls that can cause brain trauma. Although they are treated in the hospitals with subsequent rehabilitation, their weakened immune state typically affects their recovery phases. We need to develop new treatments for AD patients who have had a traumatic brain injury (TBI). This vulnerable population could be particularly amenable to precision-microbiota therapy. Although not fully understood, the brain-gut-microbiota axis plays a major role in the onset and severity of many neurological diseases. We plan to develop precision-microbiota therapy to protect against neurodegeneration and functional behavior in AD mice after TBI. The gut microbiome is emerging as an essential neuromodulator of brain-gut axis signaling. It can significantly impact brain inflammation and outcome after CNS trauma and alter anxiety- and depression-like behaviors. This research proposal is based on the scientific premise that gut bacteria can impact behavior and that brain injury can disrupt diversity in a healthy gut microbiome. The overarching hypothesis is that the gut microbiota dysfunction caused by brain trauma contributes directly to neuroinflammation and neurodegeneration responses in AD mice, and the microbiota modulation will delay the progression of AD neuropathology. Our preliminary data indicate how the microbiota of AD mice affected adversely to TBI outcomes and how probiotics help brain recovery in C57B6/J young mice. This proposal investigates the mechanistic linkage between gut microbiota and AD progression following TBI and explores potential intervention strategies. We will test this premise with the following three Specific Aims: we 1) will determine if the gut microbiome plays a role in accelerating AD pathology and cognitive decline induced by TBI, and 2) will investigate the impact of fecal transplants on AD pathology and cognitive decline after TBI, and 3) will assess the ability of multi-strain probiotics to reduce AD pathology after TBI. We expect to identify a particularly vulnerable patient population by defining which inflammatory responses associated with brain trauma accelerate AD pathogenesis and are regulated by brain-gut-microbiome signals. Our approach is significant because we will establish a “translatable” foundation for the potential of therapeutic approaches for AD after TBI by using the gut as a non-CNS target of precision-microbiota therapy.

项目总结/摘要 阿尔茨海默病（AD）是一种导致认知能力下降的进行性神经退行性疾病。的 与AD病理学相关的神经炎性事件加剧了神经变性。老年 患有痴呆症或AD的人有更高的跌倒风险，因为他们的认知功能受到影响。他们失去 他们的方向，并很容易打破他们的臀部，其他骨头，甚至更严重的福尔斯，可以导致 脑外伤虽然他们在医院接受治疗，随后进行康复，但他们的免疫力下降， 通常会影响其恢复阶段。我们需要开发新的治疗方法， 创伤性脑损伤（TBI）。这些脆弱的人群可能特别容易受到精确微生物群的影响 疗法虽然尚未完全了解，但脑-肠道-微生物群轴在发病和严重程度中起着重要作用 许多神经系统疾病。我们计划开发精确的微生物群疗法， TBI后AD小鼠的神经变性和功能行为。肠道微生物组正在成为一个重要的 脑-肠轴信号传导的神经调节剂。它可以显着影响脑炎症和CNS后的结果 创伤和改变焦虑和抑郁样行为。这项研究计划是基于科学 肠道细菌可以影响行为，脑损伤可以破坏健康肠道的多样性， 微生物组最重要的假设是脑外伤引起的肠道微生物群功能障碍 直接导致AD小鼠的神经炎症和神经变性反应， 调节将延迟AD神经病理学的进展。我们的初步数据表明， AD小鼠对TBI结果的不利影响以及益生菌如何帮助C57 B6/J年轻小鼠的大脑恢复。 该提案研究了TBI后肠道微生物群与AD进展之间的机制联系 并探索潜在的干预策略。我们将通过以下三个具体目标来检验这一前提： 我们1）将确定肠道微生物组是否在加速AD病理和认知能力下降中起作用， 2）将研究粪便移植对TBI后AD病理学和认知能力下降的影响， 和3）将评估多菌株益生菌减少TBI后AD病理的能力。我们希望能找到一个 特别是脆弱的患者群体，通过定义哪些炎症反应与脑外伤有关， 加速AD发病机制，并受脑-肠-微生物组信号调节。我们的方法意义重大 因为我们将为TBI后AD治疗方法的潜力建立一个“可翻译”的基础， 通过使用肠道作为精确微生物群治疗的非中枢神经系统靶点。