Common CD36-dependent gut-brain neuroimmune pathway regulates disruption of intestinal motility in Alzheimer's Disease

常见的 CD36 依赖性肠脑神经免疫途径调节阿尔茨海默氏病肠道运动的破坏

• 批准号: 10448209
• 负责人: Laren Becker
• 金额: $ 43.73万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448209
• 关键词: APP-PS1; Accounting; Affect; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Disease Models; Antibodies; Apoptosis; Biology of Aging; Brain; CASP3 gene; CD36 gene; Cells; Characteristics; Colon; Constipation; Cytokine Activation; Data; Dementia; Disease; Disease associated microglia; Elderly; Emotional; Enteral; Enteric Nervous System; Fecal Incontinence; Financial Hardship; Functional disorder; Gastric Emptying; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Transit; Gastrointestinal tract structure; Genetic; Human; ITGAX gene; Immune; Impairment; Individual; Inflammasome; Inflammation; Inflammatory; Injections; Interleukin-18; Interleukin-6; Intervention; Intestinal Motility; Knockout Mice; Literature; Medical; Microglia; Mus; Neurodegenerative Disorders; Neuroimmune; Neurons; PTPRC gene; Pathogenesis; Pathway interactions; Patients; Peripheral Nervous System; Phenotype; Play; Population; Process; Reporting; Research; Research Personnel; Role; Science; Senile Plaques; Signal Transduction; Small Intestines; Spinal Cord; Testing; Time; Tissues; Transgenic Mice; Tumor-infiltrating immune cells; Water; abeta accumulation; age related; brain cell; cell motility; cytokine; gastrointestinal; genetic signature; macrophage; mouse model; multidisciplinary; neuroinflammation; neuron loss; novel; preventive intervention; response; scavenger receptor; therapeutic target

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.

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， 这与胃肠动力障碍有关。这种MM改变受清道夫受体CD36的调节 并反映了在小胶质细胞中发现的AD疾病状态，小胶质细胞是大脑中的主要巨噬细胞群。 根据这些发现，我们假设在大脑和肠道中有一条共同的依赖CD36的免疫途径 调节阿尔茨海默病的神经炎症和肠道动力障碍。这一假设将通过以下方式进行检验 在AD小鼠模型(APP/PS1小鼠和Aβ-Gut注射小鼠)中联合CD36进行的两个目标 基因敲除老鼠。首先，研究人员将评估CD36的基因缺失是否会抑制Aβ诱导的 神经免疫变化的特征是MMS从组织保护性的动态平衡状态(HS)转变为有利于MMS的状态 炎症性老年状态(GS)。他们还将评估CD36缺乏是否抑制AD诱导的ENS 以免疫细胞渗入和促炎细胞因子升高为特征的神经炎症。 其次，研究人员将评估CD36缺乏对AD诱导的肠神经元丢失和 肠道动力障碍。 拟议研究的成功完成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。这一结果将为新的预防和干预措施提供信息 AD相关胃肠道疾病的治疗策略。