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

• 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
• 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' s Disease; Alzheimer' 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

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）引起慢性神经炎症伴进行性神经变性，并可能最终导致阿尔茨海默病和/或阿尔茨海默病相关痴呆和长期神经认知功能障碍。新出现的证据表明，双向脑系统的相互作用有助于这些神经病理学变化。值得注意的是，TBI会导致胃肠道（GI）病变，而GI疾病与神经功能障碍相关。我们假设脑创伤和结肠炎相互作用，促进持续的小胶质细胞失调/神经炎症，从而导致阿尔茨海默病型神经病理学的发展，并伴有进行性组织损失和认知能力下降。 TBI诱导的GI损伤是常见的，与损伤严重程度相关，可能包括粘膜损伤、肠屏障破坏和动力障碍。肠神经系统（ENS）和肠胶质细胞（EGCs）调节粘膜屏障稳态。我们报道了在小鼠中的中度受控皮质撞击（CCI），一种良好表征的实验性TBI模型，诱导EGCs胶质细胞生成/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外伤患者肠道感染风险增加的原因。此外，与未受伤动物的感染相比，TBI后慢性期的肠道感染导致结肠粘膜屏障受损增加。重要的是，肠道感染与TBI继发性损伤机制积极相互作用，并显着加剧创伤后神经炎症和相关的神经变性。 迟发性阿尔茨海默病是最常见的人类神经退行性疾病;然而，缺乏对基础过程以及疾病修饰干预措施的可用性和有效性的适当理解。阿尔茨海默病是一种多基因和环境影响的疾病，许多危险因素共同作用产生疾病过程。最强的遗传风险因素包括载脂蛋白E（APOE）的等位基因和髓样细胞2（TREM 2）基因座上表达的触发受体的点突变。临床研究发现，创伤性脑损伤（TBI）与随后发展为阿尔茨海默病的风险增加有关。此外，我们的初步数据显示，小胶质细胞，脑中主要的TREM 2表达细胞群，在TBI后经历了向活化表型的持续转变，其特征在于TREM 2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沟通，称为脑-肠轴，在神经退行性疾病中起着关键作用。因此，基于人群的队列研究表明，炎症性肠病（IBD）和随后的痴呆症的发展之间存在显着关联。重要的是，在痴呆类型中，与对照组相比，IBD患者患阿尔茨海默氏痴呆症的风险增加最大。 我们提出，轻度TBI和结肠炎协同促进慢性神经退行性过程的发展，引起迟发性中枢炎症、海马神经元丢失和神经行为功能障碍，并表现为阿尔茨海默病型神经病理学。一个关键的问题是什么潜在的机制驱动TBI后的脑-肠病理相互作用，并导致慢性神经炎症，神经变性和神经认知缺陷，导致阿尔茨海默病和/或阿尔茨海默病相关的痴呆症。拟议的研究将探讨新的概念，即针对胃肠道机制的治疗策略可能会限制脑疾病过程，包括神经变性，从而减轻TBI后慢性认知下降和阿尔茨海默病型神经病理学的发展。 我们的主要假设是：1）TBI引起脑-肠轴的慢性功能障碍，在晚期肠道攻击后引发增加的病理反应，包括分子反应如Trem 2和ApoE的小胶质细胞中的活化，已知其在阿尔茨海默病的进展中起重要作用; 2）靶向ENS/EGC或小胶质细胞活性促进脑肠稳态，减弱脑神经炎症和可能驱动阿尔茨海默病样过程的特定小胶质细胞机制，从而减少痴呆、神经变性和神经认知缺陷。 目标1：阐明小鼠TBI后慢性EGC变化的机制，并证明EGC调节剂减轻TBI后慢性期的肠道病理和神经病理。 目的2：检查ECG活性调节剂限制轻度TBI+结肠炎联合后结肠损伤和神经变性的能力。 目的3：表明轻度TBI引发中央小胶质细胞对后来的肠道挑战产生功能失调的促炎反应。