{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T16:55:19Z","timestamp":1792169719694,"version":"4.4.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Chronic cerebral hypoperfusion-induced white matter lesions are an important cause of vascular cognitive impairment in aging life. TGF-\u03b21 (transforming growth factor \u03b21) is widely recognized as a multifunctional cytokine participating in numerous pathophysiological processes in the central nervous system. In this study, we aimed to evaluate the neuroprotective potentials of TGF-\u03b21 in ischemic white matter lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>A mouse model of bilateral common carotid artery stenosis was established to imitate the ischemic white matter lesions. The agonist of the TGF-\u03b21 pathway was continuously applied via intraperitoneal injection. The Morris water maze test and gait analysis system were used to assess the cognitive and gait disorders in modeling mice. The Luxol fast blue staining, immunofluorescence, and electron microscopy were conducted to determine the severity of demyelinating lesions, microglial activation, and dysfunction of the autophagy-lysosomal pathway in microglia. Furthermore, primary cultured microglia were exposed to extracted myelin debris and TGF-\u03b21 in vitro to explore the underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>As evaluated by behavioral tests, TGF-\u03b21 significantly alleviated the cognitive dysfunction and gait disorder in bilateral common carotid artery stenosis-modeling mice. The demyelinating lesion and remyelination process were also found to be highly improved by activation of the TGF-\u03b21 pathway. The results of immunostaining and electron microscopy showed that TGF-\u03b21 could ameliorate microglial activation and the dysfunction of lipid metabolism in myelin-engulfed microglia. Mechanistically, in primary cultured microglia exposed to myelin debris, administration of TGF-\u03b21 notably mitigated the inflammatory response and accumulation of intracellular lipid droplets via promoting the lipid droplets degradation in the autophagy-lysosomal pathway, as quantified by flow cytometry, immunostaining, Western blot, etc. Yet, the application of autophagy inhibitor 3-methyladenine significantly reversed the above anti-inflammatory effects of TGF-\u03b21.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>TGF-\u03b21 relieved cognitive deficit, demyelinating lesions, and microglia-mediated neuroinflammation in bilateral common carotid artery stenosis modeling by reducing abnormal lipid droplet accumulation and dysfunction of the autophagy-lysosomal pathway in microglia. Clinically, staged activation of the TGF-\u03b21 pathway may become a potential target and promising treatment for ischemic white matter lesions and vascular cognitive impairment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.124.048206","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T08:09:36Z","timestamp":1743408576000},"page":"1554-1568","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Transforming Growth Factor \u03b21 Protects Against Ischemic Demyelination via Regulating Microglial Lipid Metabolism Pathway"],"prefix":"10.1161","volume":"56","author":[{"given":"Yi","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Neurology, Tongji Hospital, Tongji Medical College (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction Huazhong University of Science and Technology, Wuhan, China (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tongji Hospital, Tongji Medical College (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction Huazhong University of Science and Technology, Wuhan, China (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Liu","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Tongji Hospital, Tongji Medicine College (S.L.), Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tongji Hospital, Tongji Medical College (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction Huazhong University of Science and Technology, Wuhan, China (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tongji Hospital, Tongji Medical College (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction Huazhong University of Science and Technology, Wuhan, China (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tongji Hospital, Tongji Medical College (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction Huazhong University of Science and Technology, Wuhan, China (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjie","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tongji Hospital, Tongji Medical College (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., W.W.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction Huazhong University of Science and Technology, Wuhan, China (Y.X., X.W., Z.H., H.Z., Z.Y., M.X., 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