Bidirectional Brain-Gut interactions, chronic neuroinflammation and neurodegeneration after traumatic brain injury

双向脑肠相互作用、脑外伤后慢性神经炎症和神经退行性变

基本信息

批准号：
10684129
负责人：
ALAN Ira FADEN
金额：
$ 61.89万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684129
关键词：
Acute Affective Alleles Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animals Apolipoprotein E Attenuated Brain Brain Diseases Brain Pathology Cells Central Nervous System Chronic Chronic Phase Clinical Research Cognition Cognitive deficits Cohort Studies Colitis Colon Colon Injury Communication Data Dementia Development Disease Dysautonomias Electrocardiogram Encephalitis Engineering Enteral Enteric Nervous System Environment Equilibrium Functional disorder G-Protein-Coupled Receptors Gastrointestinal Diseases Gastrointestinal tract structure Genetic Hippocampus Homeostasis Human Immune Immune response Impaired cognition Impairment Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Injury Intervention Intestines Late Onset Alzheimer Disease Memory Microglia Modeling Molecular Motor Mucous Membrane Mus Nerve Degeneration Neurocognitive Neurocognitive Deficit Neurodegenerative Disorders Neuroglia Neurologic Deficit Neurologic Dysfunctions Pathologic Pathology Pathway interactions Patients Phenotype Play Point Mutation Population Predisposition Process Regulation Reporting Resistance Risk Risk Factors Role Severities TREM2 gene Therapeutic Tissues Trauma patient Traumatic Brain Injury Vagus nerve structure cholinergic clinically relevant cognitive function comparison control controlled cortical impact designer receptors exclusively activated by designer drugs enteric infection gastrointestinal genetic approach genetic risk factor glial activation gliogenesis gut homeostasis gut-brain axis improved intestinal barrier mild traumatic brain injury motility disorder neurobehavioral neuroinflammation neuron loss neuropathology neurotoxic novel overexpression permissiveness pharmacologic population based progressive neurodegeneration protective effect receptor response sex small molecule synergism transcutaneous stimulation

项目摘要

Traumatic brain injury (TBI) causes chronic neuroinflammation with progressive neurodegeneration and may ultimately lead to Alzheimer’s disease and/or Alzheimer’s Disease-related dementia and long-term neurocognitive dysfunctions. Emerging evidence suggests that bi-directional brain-systemic interactions contribute to these neuropathological changes. Notably, TBI causes gastrointestinal (GI) tract pathology and GI diseases are associated with neurological dysfunctions. We hypothesize that brain trauma and colitis interact to promote a persistent microglia dysregulation/neuroinflammation that drives the development of Alzheimer’s disease-type neuropathology with progressive tissue loss and cognitive decline. TBI-induced GI damage is common, correlates with injury severity and may include mucosal injury, intestinal barrier disruption and dysmotility. The enteric nervous system (ENS) and enteric glial cells (EGCs) regulate mucosal barrier homeostasis. We reported that moderate controlled cortical impact (CCI) in mice, a well-characterized experimental TBI model, induces increased EGCs gliogenesis/reactivity and causes delayed, chronic mucosal barrier dysfunction in the colon. These changes may explain the increased risk for enteric infections in brain trauma patients. Moreover, an enteric infection during the chronic period after TBI resulted in increased colonic mucosal barrier impairment compared to infections in non-injured animals. Importantly, the enteric infection positively interacted with TBI secondary injury mechanisms and significantly exacerbated posttraumatic neuroinflammation and related neurodegeneration. Late-onset Alzheimer’s Disease is the most common human neurodegenerative disease; however, a proper understanding of the underlaying processes as well as the availability and efficacy of disease-modifying interventions is lacking. Alzheimer’s Disease is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes. The strongest genetic risk factors include the 4 allele of apolipoprotein E (APOE4) and point mutations in triggering receptor expressed on myeloid cells 2 (TREM2) locus. Clinical studies have found that traumatic brain injury (TBI) is associated with an increased risk for subsequent development of Alzheimer’s Disease. Furthermore, our preliminary data show that microglia, the principal TREM2 expressing cell population in the brain, undergo a persistent shift toward activated phenotypes following TBI that are characterized by both TREM2 and ApoE overexpression. Intriguingly, increasing evidence suggests that reciprocal communication between the enteric and the central nervous system, termed the brain-gut axis, plays a key role in neurodegenerative disease. Thus, population-based cohort studies demonstrate a significant association between inflammatory bowel diseases (IBD) and subsequent development of dementia. Importantly, among dementia types, the risk of developing Alzheimer’s dementia demonstrated the greatest increase in IBD patients compared to controls. We propose that, mild-TBI and colitis synergize to promote the development of chronic neurodegenerative processes, causing delayed central inflammation, hippocampal neuronal loss and neurobehavioral dysfunctions and manifesting as Alzheimer’s disease-type neuropathology. A critical question is what underlying mechanisms drive the brain-gut pathological interactions after TBI and lead to chronic neuroinflammation, neurodegeneration and neurocognitive deficits that result in an Alzheimer’s disease and/or Alzheimer’s Disease-related dementia. The proposed studies will probe the novel concept that therapeutic strategies that target GI tract mechanisms may limit brain disease processes, including neurodegeneration, and thus attenuate chronic cognitive decline and the development of Alzheimer’s disease-type neuropathology after TBI. Our central hypotheses are: 1) TBI causes chronic dysfunctions in brain-gut axis, priming increased pathological responses after late enteric challenges including activation in microglia of molecular responses such as Trem2 and ApoE, which are known to play important roles in the progression of Alzheimer’s disease; 2) Targeting ENS/EGCs or microglial activity promotes brain-gut homeostasis, attenuating brain neuroinflammation and specific microglial mechanisms that may drive Alzheimer’s disease-like processes, thus reducing dementia, neurodegeneration and neurocognitive deficits. AIM1: Elucidate the mechanisms of chronic EGCs changes after mouse TBI and demonstrate that EGC modulators attenuate enteric pathology and neuropathology in the chronic phase after TBI. AIM2: Examine the ability of ECGs activity modulators to limit colon injury and neurodegeneration after combined mild-TBI+colitis. AIM3: Show that mild-TBI primes central microglia to develop a dysfunctional pro-inflammatory response to a later enteric challenge.

创伤性脑损伤（TBI）会引起慢性神经炎症，并进行性神经退行性变性，最终可能导致阿尔茨海默氏病和/或阿尔茨海默氏病与疾病相关的痴呆和长期神经认知功能障碍。新兴的证据表明，双向脑系统相互作用有助于这些神经病理学变化。值得注意的是，TBI引起胃肠道（GI）病理病理学，而GI疾病与神经功能障碍有关。我们假设脑外伤和结肠炎相互作用以促进持续的小胶质细胞失调/神经炎症，从而促进了阿尔茨海默氏病型神经病理学的发展，而逐步的组织丧失和认知能力下降。 TBI诱导的GI损伤很常见，与损伤的严重程度相关，可能包括粘膜损伤，肠道屏障破坏和运动障碍。肠神经系统（ENS）和肠神经胶质细胞（EGC）调节粘膜障碍稳态。我们报道了中度受控的皮质影响（CCI）在一种表征良好的实验性TBI模型的小鼠中诱导EGC的神经胶质发生/反应性增加，并导致结肠中延迟的慢性粘膜屏障功能障碍。这些变化可以解释脑创伤患者中启动子的风险增加。此外，与未造成的动物的感染相比，TBI后的慢性时期启动子感染导致结肠粘膜屏障障碍增加。重要的是，启动子感染与TBI二级损伤机制正相互作用，并显着加剧了创伤后神经炎症和相关神经变性。晚期的阿尔茨海默氏病是最常见的人类神经退行性疾病。但是，缺乏对基本过程以及改善疾病干预措施的可用性和有效性的正确理解。阿尔茨海默氏病是一种多基因和环境影响的疾病，其许多风险因素共同作用，以产生疾病过程。强大的遗传危险因素包括载脂蛋白E（APOE4）的4等位基因和在髓样细胞2（TREM2）基因座上表达的受体中的点突变。临床研究发现，创伤性脑损伤（TBI）与随后发展阿尔茨海默氏病的风险增加有关。此外，我们的初步数据表明，小胶质细胞（表达大脑中细胞群体的主TREM2）在TBI之后经历了向激活表型的持续转变，TBI的特征是TREM2和APOE过表达。有趣的是，越来越多的证据表明，肠道和中枢神经系统之间的相互交流称为脑肠轴，在神经退行性疾病中起关键作用。这是基于人群的队列研究表明，炎症性肠病（IBD）与随后的痴呆症之间存在显着关联。重要的是，在痴呆症类型中，与对照组相比，患阿尔茨海默氏症痴呆症的风险表明，IBD患者的增加最大。我们建议，温和的TBI和结肠炎协同促进慢性神经退行性过程的发展，导致中枢性延迟，海马神经元丧失和神经行为功能障碍，并表现为阿尔茨海默氏病的疾病型神经病理学。一个关键的问题是，什么基本机制驱动了TBI后脑核病理性相互作用，并导致慢性神经炎症，神经退行性变性和神经认知缺陷，从而导致阿尔茨海默氏病和/或阿尔茨海默氏病相关的痴呆症。拟议的研究将探讨一个新的概念，即靶向胃肠道机制的治疗策略可能会限制包括神经变性在内的脑疾病过程，从而减弱慢性认知下降以及TBI后阿尔茨海默氏病型神经病理学的发展。我们的中心假设是：1）TBI在脑肠轴上引起慢性功能障碍，在晚期肠道挑战之后增加病理反应，包括激活分子反应（例如Trem2和apoE）的小胶质细胞，这些反应在Alzheimer病的进展中起着重要作用； 2）靶向ENS/EGC或小胶质细胞活性会促进脑旋转稳态，减弱脑神经炎症和特定的小胶质细胞机制，这些机制可能会驱动阿尔茨海默氏病的类似于痴呆，从而减少痴呆，神经变性和神经认知能力。 AIM1：阐明小鼠TBI后慢性EGC的机制发生了变化，并证明EGC调节剂减弱了TBI后慢性阶段促进病理学和神经病理学。 AIM2：检查ECGS活性调节剂在合并轻度TBI+结肠炎后限制结肠损伤和神经退行性的能力。 AIM3：表明，对后来的肠子挑战产生功能障碍的促发作反应，中央小胶质细胞中心质胶质细胞中心质胶质细胞。