The interactions between myenteric macrophages and enteric neurons shape development and spread of enteric synucleinopathy

肌间巨噬细胞和肠神经元之间的相互作用影响肠突触核蛋白病的发展和扩散

• 批准号: 10723844
• 负责人: BENOIT I GIASSON
• 金额: $ 40.81万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723844
• 关键词: Acceleration; Address; Adopted; Affect; Age; Aging; Antigen Presentation; Atlases; Automobile Driving; Biological Assay; Braak' s hypothesis; Brain; Calcium; Cell Nucleus; Cells; Complement; Data; Dementia; Deposition; Development; Disease; Enteral; Etiology; Event; Excitatory Synapse; Extracellular Space; Functional disorder; Future; Genetic Transcription; Image; Immune; Immune response; Inflammatory; Inflammatory Response; Injections; Intestinal Motility; Intestines; Investigation; Lewy Body Dementia; Macrophage; Mediating; Microglia; Microscopy; Molecular; Morbidity - disease rate; Mus; Myelogenous; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Phagocytes; Phenotype; Phosphorylation; Play; Population; Prevalence; Process; Property; Resources; Risk Factors; Role; Sentinel; Shapes; Source; Stomach; Synapses; Synaptic Transmission; T-Cell Activation; Testing; Therapeutic; Time; Vagus nerve structure; Work; afferent nerve; alpha synuclein; brain pathway; economic cost; insight; motility disorder; mouse model; multi-photon; network dysfunction; neurophysiology; novel; patch clamp; response; single-cell RNA sequencing; socioeconomics; synaptic pruning; synucleinopathy; uptake

Lewy Body Dementia, and Parkinson disease (PD)-dementia, are characterized by neurodegeneration associated with synucleinopathies, such as deposition of misfolded α-synuclein (αsyn). Synucleinopathy of the CNS is often accompanied or preceded by synucleinopathy in the gut, and associated gut dysfunction is a significant source of morbidity in aging related neurodegeneration. The Braak hypothesis suggests that misfolded αsyn in enteric neurons can spread to the brain via the Vagus nerve with age resulting in a spectrum of disorders ranging from PD to Lewy Body Dementia. By this hypothesis, the presence and degree of enteric neuron pathology and dysfunction is a sentinel event in the pathogenesis of αsyn-associated disorders and dementias. Yet, our understanding of the cellular and molecular mechanisms driving enteric synucleinopathy remains limited. One factor to consider is the immune response. While it’s been postulated that myenteric macrophages, like microglia, may try to clear αsyn, this has not been studied. Thus, the myenteric macrophage response to αsyn represents an underexplored component of enteric synucleinopathy, and by extension, of the gut-to-brain hypothesis of neurodegenerative diseases, and Lewy Body Dementia etiology. Of the many types of macrophages, this proposal focusses on myenteric nerve-associated macrophages and how they affect enteric neuron pathology and dysfunction in the proposed gut-to-brain pathway. The objective of this study is to investigate how the interactions between myenteric macrophages and neurons influence the development and spread of enteric synucleinopathy potentially via the vagus nerve afferent. We will test the hypothesis that myenteric macrophages engage a pro-phagocytic phenotype to clear enteric neuronal αsyn that initially limits pathology but leads to excessive synaptic elimination and neuronal dysfunction (enteric neurons and vagus nerve). The completion of proposed studies will reveal 1) the dynamics of macrophage responses to gut synucleinopathy, 2) determine the contribution of macrophage uptake and clearance in mitigating phosphorylated αsyn pathology in enteric neurons, 3) determine the molecular relationship between enteric neuronal network dysfunction and macrophage-mediated synapse elimination in a mouse model of enteric synucleinopathy and 4) Identify the mechanisms by which gut-seeded syn affects gut-brain vagal circuits. These studies can lead to new insights on how to therapeutically engage the spread of αsyn starting in the gut and result in Lewy Body Dementia.

路易体痴呆和帕金森病 (PD) 痴呆的特征是与突触核蛋白病相关的神经变性，例如中枢神经系统的错误折叠 α-突触核蛋白 (αsyn) 沉积通常伴随或先于肠道中的突触核蛋白病，并与之相关。肠道功能障碍是衰老相关神经退行性疾病发病的一个重要来源。布拉克假说表明，肠神经元中错误折叠的 αsyn 可以扩散到大脑。随着年龄的增长，迷走神经会导致一系列疾病，从帕金森病到路易体痴呆。根据这一假设，肠神经元病理和功能障碍的存在和程度是αsyn相关疾病和痴呆发病机制中的一个前哨事件。 ，我们对驱动肠突触核蛋白病的细胞和分子机制的了解仍然有限，但需要考虑的一个因素是免疫反应，尽管人们推测肌间巨噬细胞（如小胶质细胞）可能会尝试清除αsyn，因此，肌间巨噬细胞对 αsyn 的反应代表了肠道突触核蛋白病的一个尚未充分研究的组成部分，并且延伸到了神经退行性疾病的肠到脑假说和多种类型的巨噬细胞的路易体痴呆病因学中。 ，该提案重点关注肌间神经相关巨噬细胞以及它们如何影响所提出的肠-脑通路中的肠神经元病理和功能障碍。肌间巨噬细胞和神经元之间的相互作用如何通过迷走神经传入影响肠突触核蛋白病的发展和传播，我们将检验肌间巨噬细胞利用促吞噬表型来清除肠神经元αsyn的假设，该αsyn最初限制病理学但导致过度。突触消除和神经元功能障碍（肠神经元和迷走神经）。拟议研究的完成将揭示1）巨噬细胞对肠道突触核蛋白病的反应动力学， 2) 确定巨噬细胞摄取和清除在减轻肠神经元磷酸化 αsyn 病理学中的贡献，3) 确定肠神经元网络功能障碍与肠突触核蛋白病小鼠模型中巨噬细胞介导的突触消除之间的分子关系，4) 确定机制哪些肠道种子 Syn 影响肠脑迷走神经回路，这些研究可以为如何治疗性地参与 αsyn 在肠道中的传播提供新的见解。路易体痴呆。