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

路易体痴呆和帕金森病(PD)-痴呆的特点是神经退行性变与突触核蛋白病变相关，如错误折叠的α-突触核蛋白（αsyn）沉积。中枢神经系统突触核蛋白病常伴随或先于肠道突触核蛋白病，相关的肠道功能障碍是衰老相关神经变性发病的重要来源。Braak假说认为，随着年龄的增长，肠道神经元中错误折叠的α - syn可以通过迷走神经扩散到大脑，从而导致从PD到路易体痴呆等一系列疾病。根据这一假设，肠神经元病理和功能障碍的存在和程度是α -突触相关疾病和痴呆发病机制中的前哨事件。然而，我们对驱动肠突触核蛋白病的细胞和分子机制的理解仍然有限。需要考虑的一个因素是免疫反应。虽然假设肌肠巨噬细胞，像小胶质细胞一样，可能试图清除αsyn，但这还没有得到研究。因此，肌肠巨噬细胞对αsyn的反应代表了肠突触核蛋白病的一个未被探索的组成部分，进而延伸到神经退行性疾病的肠-脑假说和路易体痴呆病因学。在众多类型的巨噬细胞中，本研究主要关注肌肠神经相关巨噬细胞，以及它们如何影响肠神经元病理和肠-脑通路的功能障碍。本研究的目的是探讨肌肠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。我们将验证肌肠巨噬细胞参与前吞噬表型来清除肠神经元αsyn的假设，这种αsyn最初限制了病理，但会导致过度的突触消除和神经元功能障碍（肠神经元和迷走神经）。这些研究的完成将揭示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病理中的作用。3)在小鼠肠突触核蛋白病模型中确定肠神经网络功能障碍与巨噬细胞介导的突触消除之间的分子关系；4)确定肠种子突触影响肠-脑迷走神经回路的机制。这些研究可以为如何治疗αsyn从肠道开始扩散并导致路易体痴呆提供新的见解。

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.