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: 10517782
• 负责人: ALAN Ira FADEN
• 金额: $ 61.73万
• 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/10517782
• 关键词: Acute; Affective; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animals; Apolipoprotein E; Attenuated; Brain; Brain Diseases; Brain Pathology; Cells; 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; Equilibrium; Functional disorder; G-Protein-Coupled Receptors; Gastrointestinal Diseases; Gastrointestinal tract structure; Hippocampus (Brain); Homeostasis; Human; Immune; Immune response; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intervention; Intestines; Late Onset Alzheimer Disease; Lead; Memory; Microglia; Modeling; Molecular; Motor; Mucous Membrane; Mus; Nerve Degeneration; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neuroglia; Neurologic Deficit; Neurologic Dysfunctions; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Point Mutation; Population; 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; controlled cortical impact; designer receptors exclusively activated by designer drugs; enteric infection; gastrointestinal; 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; population based; progressive neurodegeneration; protective effect; receptor; response; sex; small molecule; 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退行性变，最终可能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，双向脑系统相互作用有助于这些神经病理变化。值得注意的是，创伤性脑损伤引起胃肠道病理，而胃肠道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，促进持续的小胶质细胞失调/神经炎症，从而驱动阿尔茨海默病型神经病理学的发展，伴有进行性组织丧失和认知能力下降。