Altered ENS Neuroimmune Interactions Disrupt Gastrointestinal Motility in Alzheimers Disease

摘要 包括便秘和大便失禁在内的胃肠道（GI）疾病常见于以下患者： 阿尔茨海默病（AD）是痴呆症最常见的原因。这些疾病也经常 在老年人中遇到，提高了一个共同的过程可能是两者肠道紊乱的基础的可能性。 AD和老化。在AD患者和AD动物模型中，淀粉样蛋白-β（Aβ）斑块，疾病标志之一， 肠神经系统（ENS）是周围神经系统的一个自主分支 跨越胃肠道并调节肠道运动的系统。Aβ肠道蓄积似乎导致ENS 神经炎症和肠道收缩力受损，但目前的文献排除了明确的结论。是否 以及AD如何涉及肠道越来越重要，因为新出现的报告表明， 疾病会从肠道传播到大脑拟议的多学科研究将结合 AD科学与衰老的基础生物学。我们发现肌层的年龄相关变化 巨噬细胞（巨噬细胞），ENS中的组织驻留巨噬细胞群体，驱动老年ENS炎症， 其与GI运动的破坏和认知受损有关。这种MM改变取决于 微生物群中的因子，并反映了在小胶质细胞中发现的AD疾病状态， 大脑的人口。根据这些发现，我们认为AD引起的MM变化与 在老年受试者中观察到，导致ENS神经炎症、GI运动改变和受损 认知，并依赖于宿主-微生物群的相互作用。我们将从三个方面来检验这一假设 在APP/PS1 AD小鼠模型中进行。首先，研究人员将评估AD是否会导致ENS 神经免疫变化，其特征在于MM老年病状态（GDS）。他们将评估是否 ESTA的改变导致老年ENS神经炎症与免疫细胞浸润和升高的前 炎性细胞因子和肠神经元损失。其次，调查人员将评估是否中断 肠道运动先于认知受损。最后，使用微生物群的实验操作， 研究人员将探索宿主-微生物群相互作用在AD相关胃肠道疾病中的作用， 与认知的关系。具体来说，研究人员将检查AD疾病是否以及如何进展， 受慢性抗生素、来自年轻或年老小鼠的粪便的粪便微生物群移植或益生菌的影响 补充嗜粘蛋白阿克曼氏菌（Akkermansia mucinophila），这是老年小鼠中减少的微生物群组分。 成功完成拟议的研究将确定关键的病理生理途径，影响 肠道和认知能力下降之前。这些结果将为AD的新预防和干预策略提供信息 和老年痴呆症

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.