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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

抽象的胃肠道（GI）疾病，包括便秘和大便失禁，常见于患有以下疾病的患者：阿尔茨海默病 (AD) 是痴呆症的最常见原因，这些疾病也很常见。在老年人中，这增加了一种可能性，即共同的过程可能是导致两者肠道紊乱的原因 AD 和衰老。在患有 AD 的人类和 AD 动物模型中，β 淀粉样蛋白 (Aβ) 斑块是该疾病的标志之一，已在肠神经系统 (ENS) 中检测到，肠神经系统是周围神经系统的一个自主分支跨越胃肠道并调节肠道蠕动的系统 Aβ 肠道积聚似乎会导致 ENS。神经炎症和肠道收缩力受损，但目前的文献排除了是否有明确的结论。鉴于神经退行性疾病的新报告不断出现，AD 如何影响肠道变得越来越重要拟议的多学科研究将整合这些疾病。 AD 科学与衰老的基本生物学相结合我们发现与年龄相关的肌层变化。巨噬细胞 (MM) 是 ENS 中组织驻留的巨噬细胞群，可驱动老年 ENS 炎症，这与胃肠道运动的破坏有关，这种 MM 改变是由清道夫受体 CD36 调节的。并反映了小胶质细胞（大脑中主要的巨噬细胞群）中发现的 AD 疾病状态。根据这些发现，我们假设大脑和肠道中常见的 CD36 依赖性免疫途径 ENS 调节 AD 中的神经炎症和肠道蠕动的破坏。这一假设将得到检验。结合 CD36 在 AD 小鼠模型（APP/PS1 小鼠和 Aβ 肠道注射小鼠）中执行两个目标首先，研究人员将评估 CD36 的基因缺失是否会抑制 Aβ 诱导。神经免疫变化的特征是 MM 从组织保护性稳态 (HS) 转变为促免疫状态 (HS)。他们还将评估 CD36 缺乏是否会抑制 AD 诱导的 ENS。以免疫细胞浸润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 缺陷对 AD 诱导的肠神经元损失的影响，以及破坏肠道蠕动。成功完成拟议的研究将确定大脑和肠道的关键病理生理学途径研究结果将为新的预防和干预提供信息。 AD 相关胃肠道疾病的策略。