{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:32:46Z","timestamp":1787877166925,"version":"build-2784847793"},"reference-count":54,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:00:00Z","timestamp":1749340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences","award":["2021-I2M-1-034"],"award-info":[{"award-number":["2021-I2M-1-034"]}]},{"name":"Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences","award":["2023-PT180-01"],"award-info":[{"award-number":["2023-PT180-01"]}]},{"name":"Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences","award":["82161138027"],"award-info":[{"award-number":["82161138027"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences","award":["2021-I2M-1-034"],"award-info":[{"award-number":["2021-I2M-1-034"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences","award":["2023-PT180-01"],"award-info":[{"award-number":["2023-PT180-01"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences","award":["82161138027"],"award-info":[{"award-number":["82161138027"]}]},{"name":"National Natural Science Foundation of China","award":["2021-I2M-1-034"],"award-info":[{"award-number":["2021-I2M-1-034"]}]},{"name":"National Natural Science Foundation of China","award":["2023-PT180-01"],"award-info":[{"award-number":["2023-PT180-01"]}]},{"name":"National Natural Science Foundation of China","award":["82161138027"],"award-info":[{"award-number":["82161138027"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Abnormal deposition of \u03b2-amyloid (A\u03b2) is a core pathological feature of Alzheimer\u2019s disease (AD). Syndecan-3 (SDC3), a type I transmembrane heparan sulfate proteoglycan (HSPG), is abnormally overexpressed in the brains of AD patients and model animals, specifically accumulating in the peri-plaque region of amyloid plaques. However, its regulatory mechanism in the process of A\u03b2 deposition remains unclear. This study aims to clearly define the role of SDC3 in A\u03b2 aggregation and neuroinflammation, two critical processes in AD pathogenesis. Specifically, we investigate how SDC3 modulates A\u03b2 aggregation and its interaction with neuroinflammatory pathways, which may contribute to the progression of AD. By elucidating the mechanisms underlying SDC3\u2019s involvement in these processes, we seek to provide new insights into potential therapeutic targets for AD. In this study, a 5\u00d7FAD mouse model with downregulated SDC3 expression was constructed. Behavioral assessments and synaptic function tests were performed to explore the effects of SDC3 on cognition in 5\u00d7FAD mice. Immunofluorescence co-localization technology was utilized to analyze the pathological co-deposition of SDC3 and A\u03b2 in the hippocampus, cortex, and meningeal blood vessels. Quantitative assessments of pro-inflammatory cytokines such as Tnf-\u03b1 and Cxcl10 in the brain were performed through histopathological analysis combined with qPCR. Western blotting was used to examine the phosphorylation status of STAT1\/STAT3 and the expression changes of IBA1\/GFAP to systematically analyze the molecular mechanisms through which SDC3 regulates AD pathology. This study revealed that SDC3 expression was significantly upregulated in the brain regions of the 5\u00d7FAD model mice and co-localized pathologically with A\u03b2. Cell lineage tracing analysis showed that the elevated SDC3 expression primarily originated from glial cells. Behavioral and pathological results demonstrated that downregulation of SDC3 significantly improved cognitive dysfunction in the model mice and effectively reduced the A\u03b2 burden in the brain. Molecular mechanism studies showed that downregulation of SDC3 reduced the phosphorylation of STAT1 and STAT3, thereby inhibiting the activation of the JAK-STAT and cGAS-STING signaling pathways, reducing the activation of microglia\/astrocytes and suppressing the expression of pro-inflammatory cytokines such as Tnf-\u03b1 and Cxcl10. This study reveals that SDC3 co-localizes with A\u03b2 pathology and synergistically exacerbates neuroinflammation. Knockdown of SDC3 can simultaneously reduce both A\u03b2 deposition and the release of inflammatory factors from glial cells. Mechanistic research indicates that SDC3 drives a \u201cglial activation\u2013cytokine release\u201d vicious cycle through the JAK-STAT and cGAS-STING signaling pathways. These findings suggest that SDC3 may serve as a key hub coordinating amyloid pathology and neuroinflammation in AD, providing new insights for the development of combination therapies targeting the HSPG network.<\/jats:p>","DOI":"10.3390\/ijms26125502","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T06:46:01Z","timestamp":1749451561000},"page":"5502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Co-Aggregation of Syndecan-3 with \u03b2-Amyloid Aggravates Neuroinflammation and Cognitive Impairment in 5\u00d7FAD Mice"],"prefix":"10.3390","volume":"26","author":[{"given":"Fan","family":"Ye","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingfeng","family":"Li","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghan","family":"Wu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Tian","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanju","family":"Gong","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Cao","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingtai","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Human Disease Comparative 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