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

创伤性脑损伤会导致慢性神经炎症和进行性神经变性，最终可能导致阿尔茨海默病和/或阿尔茨海默病相关的痴呆和长期的神经认知功能障碍。新出现的证据表明，脑-系统双向相互作用导致了这些神经病理变化。值得注意的是，脑外伤导致胃肠道(GI)病理，胃肠道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调节失调/神经炎症，从而推动阿尔茨海默病类型神经病理的发展，导致进行性组织丢失和认知能力下降。 颅脑损伤引起的胃肠道损伤是常见的，与损伤严重程度相关，可能包括粘膜损伤、肠屏障破坏和运动障碍。肠神经系统(ENS)和肠神经胶质细胞(EGCs)调节粘膜屏障的动态平衡。我们报道，在小鼠中，中度控制性皮质撞击(CCI)是一种具有良好特征的实验性TBI模型，它诱导EGCs胶质生成/反应性增加，并导致延迟的、慢性的结肠粘膜屏障功能障碍。这些变化可能解释了脑外伤患者肠道感染风险增加的原因。此外，与未受伤的动物相比，TBI后慢性期的肠道感染导致结肠粘膜屏障损伤增加。重要的是，肠道感染与颅脑损伤的继发性损伤机制正相关，并显著加剧了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人类最常见的神经退行性疾病；然而，对其潜在过程以及疾病修正干预措施的有效性和有效性缺乏适当的了解。阿尔茨海默病是一种多基因的、受环境影响的疾病，有许多危险因素共同作用，产生疾病过程。最大的遗传危险因素包括载脂蛋白E的4等位基因(4)和髓系细胞表达的受体2(TREM2)基因座的点突变。临床研究发现，创伤性脑损伤(TBI)与阿尔茨海默病后续发展的风险增加有关。此外，我们的初步数据显示，脑内主要表达TREM2的小胶质细胞在脑损伤后经历了持续的向激活表型的转变，其特征是TREM2和ApoE的过度表达。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通信，即脑-肠轴，在神经退行性疾病中发挥着关键作用。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著的相关性。重要的是，在痴呆症类型中，与对照组相比，IBD患者患阿尔茨海默氏症的风险增加最多。 我们认为，轻度颅脑损伤和结肠炎协同作用促进慢性神经退行性变过程的发展，导致延迟的中枢性炎症、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类型的神经病理。一个关键的问题是，什么潜在的机制驱动了脑-肠道损伤后的病理相互作用，并导致慢性神经炎、神经变性和神经认知缺陷，从而导致阿尔茨海默病和/或阿尔茨海默病相关痴呆。拟议的研究将探索一种新的概念，即针对胃肠道机制的治疗策略可能会限制包括神经退化在内的大脑疾病过程，从而减缓脑损伤后慢性认知能力下降和阿尔茨海默病类型神经病理的发展。 我们的中心假设是：1)脑损伤导致脑肠轴的慢性功能障碍，启动晚期肠道挑战后的病理反应增加，包括激活小胶质细胞中已知在阿尔茨海默病的进展中发挥重要作用的分子反应，如TREM2和ApoE；2)靶向ENS/EGCs或小胶质细胞活动促进脑肠稳态，减轻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机制，从而减少痴呆、神经变性和神经认知缺陷。 目的：阐明小鼠颅脑损伤后慢性EGCs改变的机制，证明EGC调节剂减轻了脑创伤后慢性期的肠道病理和神经病理。 目的：检测ECGs活性调节剂在限制轻度TBI结肠炎后结肠损伤和神经退行性变方面的能力。 目的：显示轻度创伤性脑损伤可激活中央小胶质细胞，使其对以后的肠道攻击产生功能失调的促炎反应。

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.