Altered ENS Neuroimmune Interactions Disrupt Gastrointestinal Motility in Alzheimers Disease

摘要 胃肠道(GI)疾病包括便秘和大便失禁，常见于 阿尔茨海默病(AD)是导致痴呆症的最常见原因。这些同样的障碍也经常 在老年人中遇到，增加了共同的过程可能是两者肠道障碍的基础 AD和衰老。在患有AD和AD动物模型的人类中，淀粉样蛋白-β(Aβ)斑块是疾病的标志之一， 在肠神经系统(ENS)中被检测到，肠神经系统是周围神经的一个自主分支 横跨胃肠道并调节肠道运动的系统。β肠道蓄积似乎会导致ENS 神经炎症和肠道收缩功能受损，但目前的文献排除了明确的结论。是否 鉴于新出现的关于阿尔茨海默病神经退行性变的报道，阿尔茨海默病如何涉及肠道变得越来越重要 疾病从肠道传播到大脑。拟议的多学科研究将整合 阿尔茨海默病的科学与衰老的基本生物学。我们发现，与年龄相关的肌肉变化 巨噬细胞(MMS)，一组驻留在ENS中的组织巨噬细胞，推动老年ENS炎症， 这与胃肠动力障碍和认知受损有关。此MM更改取决于 微生物区系中的因素，反映了在小胶质细胞中发现的AD疾病状态，小胶质细胞是主要的巨噬细胞 大脑的种群。根据这些发现，我们假设AD引起的MM变化类似于 见于老年受试者，导致ENS神经炎症，胃肠动力改变和受损 认知，并依赖于宿主-微生物区系的相互作用。这一假设将通过三个目标进行检验 在APP/PS1 AD鼠标模型中执行。首先，调查人员将评估AD是否会导致ENS 以MM老年病状态(GDS)为特征的神经免疫变化。他们将评估是否 MMS的改变导致老年性ENS神经炎症，伴有免疫细胞的渗透和PRO的升高 炎性细胞因子和肠神经细胞丢失。其次，调查人员将评估 肠道运动先于认知受损。最后，使用对微生物区系的实验操作， 研究人员将探索宿主-微生物区系相互作用在AD相关胃肠道疾病中的作用及其 与认知的关系。具体地说，研究人员将检查AD疾病是否以及如何进展 会受到慢性抗生素、幼鼠或老年鼠粪便微生物区系移植或益生菌的影响 补充阿克曼嗜粘菌，这是一种减少老年小鼠体内微生物区系的成分。 成功完成拟议的研究将确定影响血管生成的关键病理生理途径 直觉和先于认知能力下降。这一结果将为AD的预防和干预策略提供新的信息 以及与衰老相关的痴呆症。

Abstract Gastrointestinal (GI) disorders including constipation and fecal incontinence are commonly found in patients with Alzheimer’s disease (AD), the most common cause of dementia. These same disorders are also frequently encountered in the elderly, raising the possibility that a common process may underlie gut disturbances for both AD and aging. In humans with AD and AD animal models, amyloid-β (Aβ) plaques, one of the disease hallmarks, have been detected in the enteric nervous system (ENS), an autonomous branch of the peripheral nervous system that spans the GI tract and regulates gut motility. Aβ gut accumulation appears to cause ENS neuroinflammation and impaired gut contractility but current literature precludes definitive conclusion. Whether and how AD involves the gut is of increasing importance given emerging reports that neurodegenerative disorders are transmitted from the gut to the brain. The proposed multidisciplinary study will integrate the science of AD with the basic biology of aging. We found that age-related changes to muscularis macrophages (MMs), a population of tissue-resident macrophages in the ENS, drive geriatric ENS inflammation, which is associated with disruption of GI motility and impaired cognition. This MM alteration is dependent on factors in the microbiota and mirrors an AD diseased state found in microglia, the predominant macrophage population of the brain. Following on these findings, we posit that AD causes MM changes similar to those seen in geriatric subjects that result in ENS neuroinflammation, altered GI motility and impaired cognition, and depend on host-microbiota interactions. This hypothesis will be tested with three aims performed in the APP/PS1 AD mouse model. First, the investigators will evaluate whether AD causes ENS neuroimmune changes characterized by a MM geriatric disease state (GDS). They will assess whether alterations in MMs lead to geriatric ENS neuroinflammation with infiltration of immune cells and elevated pro- inflammatory cytokines, and enteric neuronal loss. Second, the investigators will assess whether disruption in gut motility precedes impaired cognition. Finally, using experimental manipulation of the microbiota, the investigators will explore the role of host-microbiota interactions in AD-associated GI disease and their relationship to cognition. Specifically, the investigators will examine whether and how AD disease progression is affected by chronic antibiotics, fecal microbiota transplantation of stool from young or old mice, or probiotic supplementation with Akkermansia mucinophila, a microbiota component reduced in old mice. Successful completion of the proposed studies will identify critical pathophysiological pathways that affect the gut and precede cognitive decline. The results will inform novel prevention and intervention strategies for AD and aging-associated dementia.