PROJECT SUMMARY Lewy Body Dementia (LBD) and Parkinson's disease (PD) are pathologically characterized by the presence of Lewy bodies, composed of misfolded alpha synuclein (α-syn) inclusions. These disorders are progressive, and result from the degeneration of dopaminergic neurons in multiple motor and non-motor basal ganglia circuits. While the current gold standard treatment for PD is dopamine replacement therapy, it only addresses motor symptoms, and over time results in motor fluctuations and dyskinesias. Hence there is an unmet need for delivering viable treatments after inexorable disease onset in syncleinopathies such as LBD and PD. In this proposal, we will target α-syn deposition and neuronal death via a unique, immunomodulatory approach in an animal model at two different time points after initiation of pathology in Aim 1, and assess immune markers involved in ACT in Aim 2. There is evidence suggesting that microbial dysbiosis can influence host immune function and that gut microbiota could play a role in immunotherapy efficacy in several cancers. This demonstrates the existence of a crosstalk between host immunity and microbiota. Hence, we will also assess if there is an impact of ACT on gut microbiota after pathology has initiated, and whether microbiota play a role in efficacy of our immunotherapy in Aim 3. Ultimately, findings from this innovative and novel study will pave the way for applying immunomodulatory therapies in Lewy body dementias and other synucleinopathies and delivering commensal microbiota as therapeutic adjuvants.