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。

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目概要/摘要阿尔茨海默病（AD）是一种进行性神经退行性疾病，会导致认知能力下降。与 AD 病理相关的神经炎症事件加剧了老年人的神经变性。患有痴呆症或 AD 的人跌倒的风险更高，因为他们的认知功能受到影响。他们的方向很容易折断臀部、其他骨头，甚至更严重的跌倒，可能导致尽管他们在医院接受治疗并进行康复治疗，但他们的免疫系统仍然受到削弱。状态通常会影响他们的恢复阶段，我们需要为患有 AD 的患者开发新的治疗方法。创伤性脑损伤（TBI）这一弱势群体可能特别容易受到精准微生物群的影响。尽管尚未完全了解，但脑-肠-微生物轴在发病和严重程度中起着重要作用。我们计划开发精准微生物疗法来预防许多神经系统疾病。 TBI 后 AD 小鼠的神经退行性疾病和功能行为正在成为一个重要因素。脑肠轴信号传导的神经调节剂可以显着影响中枢神经系统术后的脑部炎症和结果。该研究提案基于科学。前提是肠道细菌会影响行为，而脑损伤会破坏健康肠道的多样性首要的假设是肠道微生物群功能障碍是由脑损伤引起的。直接导致 AD 小鼠的神经炎症和神经退行性反应，以及微生物群我们的初步数据表明微生物群如何调节AD神经病理学的进展。 AD 小鼠对 TBI 结局产生不利影响，以及益生菌如何帮助 C57B6/J 幼鼠的大脑恢复。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讨潜在的干预策略，我们将通过以下三个具体目标来测试这一前提：我们 1) 将确定肠道微生物组是否在加速 AD 病理和诱发的认知能力下降中发挥作用 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， 3) 将评估多菌株益生菌减少 TBI 后 AD 病理的能力。通过定义与脑外伤相关的炎症反应来识别特别脆弱的患者群体加速 AD 发病机制并受到脑-肠-微生物信号的调节，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“可转化”基础通过使用肠道作为精准微生物群治疗的非中枢神经系统目标。