Common CD36-dependent gut-brain neuroimmune pathway regulates disruption of intestinal motility in Alzheimer's 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， 这与胃肠道运动的破坏有关。这种MM改变受清道夫受体CD 36调节 并且反映了在小胶质细胞中发现的AD疾病状态，小胶质细胞是大脑的主要巨噬细胞群体。 根据这些发现，我们认为脑和肠道中共同的CD 36依赖性免疫途径 ENS调节AD中的神经炎症和肠动力的破坏。这一假设将得到检验， 在AD小鼠模型（APP/PS1小鼠和Aβ肠注射小鼠）中进行了两个目的， 敲除小鼠首先，研究人员将评估CD 36基因缺失是否抑制Aβ诱导的 神经免疫变化的特点是从组织保护，稳态（HS）的转变， 炎症性老年状态（GS）。他们还将评估CD 36缺陷是否抑制AD诱导的ENS 神经炎症，其特征在于免疫细胞浸润和促炎细胞因子升高。 其次，研究人员将评估CD 36缺乏对AD诱导的肠神经元丢失的影响， 破坏肠道动力。 成功完成拟议的研究将确定大脑和肠道的关键病理生理途径 与神经退行性疾病和衰老有关研究结果将为新的预防和干预提供信息 AD相关GI疾病的治疗策略。

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. This MM alteration is regulated by the scavenger receptor CD36 and mirrors an AD diseased state found in microglia, the predominant macrophage population of the brain. Following on these findings, we posit that a common CD36-dependent immune pathway in brain and gut regulates ENS neuroinflammation and disruption of gut motility in AD. This hypothesis will be tested with two aims performed in AD mouse models (APP/PS1 mice and Aβ-gut injected mice) in combination with CD36 knockout mice. First, the investigators will evaluate whether genetic deletion of CD36 inhibits Aβ induced neuroimmune changes characterized by a shift in MMs from a tissue-protective, homeostatic state (HS) to a pro- inflammatory geriatric state (GS). They will also assess whether CD36 deficiency inhibits AD-induced ENS neuroinflammation characterized by infiltration of immune cells and elevated pro-inflammatory cytokines. Second, the investigators will assess the impact of CD36 deficiency on AD-induced enteric neuron loss and disruption of gut motility. Successful completion of the proposed studies will identify a critical pathophysiological pathway in brain and gut involved in neurodegenerative disease and aging. The results will inform novel prevention and intervention strategies for AD-associated GI disorders.