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In this study, we identified an abnormal increase in lysophosphatidylcholine (LPC) levels in PD patients, which closely correlates with the severity of cognitive impairment. LPC disrupts the miR\u20102885\/TDP\u201043 signaling pathway in microglia, driving dopaminergic presynaptic engulfment. In LPC\u2010exposed mice, microglial activation via miR\u20102885\/TDP\u201043\/p65 signaling led to inflammatory cytokine and complement release, marking dopaminergic synapses for phagocytosis with a \u201cPS\/C1q\u201d signal. Following the inhibition of LPC\u2010induced microglial activation through chemogenetic methods, we observed a significant reduction in the phagocytosis of dopaminergic synapses, resulting in improved executive function. The miR\u20102885 disrupted LPC\u2010induced dopaminergic phagocytosis and alleviated EDF. Furthermore, the accumulation of excessive TDP\u201043 due to the loss of miR\u20102885 promoted the engulfment of dopaminergic synapses by facilitating the entry of p65 into the nucleus. Inhibiting TDP\u201043 levels effectively mitigated LPC\u2010induced EDF. Additionally, supplementing dopamine receptor agonists enhanced the excitability of regional glutamatergic neurons, leading to improved executive function. In summary, LPC exposure in the mPFC impairs microglial regulation, leading to dopaminergic synaptic loss and underactivity of glutamatergic neurons. These changes drive the development of executive dysfunction in PD.<\/jats:p>","DOI":"10.1111\/acel.70003","type":"journal-article","created":{"date-parts":[[2025,2,15]],"date-time":"2025-02-15T12:20:01Z","timestamp":1739622001000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Enhanced Microglial Engulfment of Dopaminergic Synapses Induces Parkinson's Disease\u2010Related Executive Dysfunction in an Acute <scp>LPC<\/scp> Infusion Targeting the <scp>mPFC<\/scp>"],"prefix":"10.1111","volume":"24","author":[{"given":"Yehao","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology Xuzhou Medical University  Xuzhou Jiangsu China"},{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology Xuzhou Medical University  Xuzhou Jiangsu China"},{"name":"Department of Neurology The Second People's Hospital of Huai'an and the Affiliated Huai'an Hospital of Xuzhou Medical University  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology Xuzhou Medical University  Xuzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Diao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology Xuzhou Medical University  Xuzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurong","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology Xuzhou Medical University  Xuzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology Xuzhou Medical University  Xuzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology Xuzhou Medical University  Xuzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Neurology Shanghai Xuhui Central Hospital, Zhongshan\u2010Xuhui Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5500-8419","authenticated-orcid":false,"given":"Chuanxi","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology Xuzhou Medical University  Xuzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.22360"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2626-6"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg4980"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.06.012"},{"issue":"3","key":"e_1_2_9_6_1","first-page":"186","article-title":"S\u2010Adenosyl\u2010L\u2010Methionine Decreases Motor Activity in the Rat: Similarity to Parkinson's Disease\u2010Like Symptoms","volume":"59","author":"Crowell B. 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