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.