{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:35:43Z","timestamp":1787009743600,"version":"build-2736575974"},"reference-count":49,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,9,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Diabetes\u2010related cerebral small\u2010vessel disease (CSVD) is an important causative factor of cognitive impairment, but its molecular mechanisms have not been clarified. The aim of this study was to investigate the role of the necrotic apoptotic pathway (RIP1\/RIP3\/MLKL) and the inflammatory response in diabetic CSVD. Wild\u2010type C57BL\/6 mice and leptin receptor\u2010deficient db\/db mice were categorized into six groups according to age (8\u2010, 12\u2010, and 16\u2010week time points) and genotype. Cognitive function was assessed by the water maze experiment (escape latency, percentage of time spent in the target quadrant, and number of times through the table); cerebral atrophy and ventricular dilatation were detected by cranial MRI; cerebral microvascular structure, cortical neuronal damage, and ultrapathological changes in hippocampal mitochondria were observed by HE staining and transmission electron microscopy, respectively; and blood\u2013brain barrier\u2010associated proteins were detected by western blot and RT\u2010qPCR (occludin, ZO\u20101, VEGFA) and necroptotic apoptotic pathway molecules (RIP1, RIP3, MLKL). Western blot and RT\u2010qPCR were used to detect the protein and mRNA expression of blood\u2013brain barrier\u2010associated proteins (occludin, ZO\u20101, VEGFA) and necroptotic apoptotic pathway molecules (RIP1, RIP3, MLKL). Immunohistochemistry was used to localize the distribution of RIP1\/RIP3\/MLKL in the brain tissues; and plasma levels of inflammatory factors (IL\u20106, IL\u201010, TNF\u2010\u03b1, NF\u2010\u03baB) were quantified by ELISA. In db\/db mice: (1) spatial learning and memory abilities were reduced compared to wild\u2010type (WT) mice; (2) at 16\u2009weeks of age, db\/db mice showed signs of temporal lobe atrophy and an enlarged fourth cerebral ventricle; (3) capillary proliferation and cortical injury were observed in the frontal cortex, along with mitochondrial swelling, degeneration, and nuclear membrane rupture in hippocampal cells; (4) the occludin and ZO\u20101 protein expression in the db\/db\u201016W group decreased to 0.48\u2010 and 0.68\u2010fold of the WT\u20108W group, respectively, and the VEGFA was elevated by 2.87\u2010fold; the mRNA expression of RIP1\/RIP3\/MLKL was up\u2010regulated to 3.02\u2010, 3.12\u2010, and 4.02\u2010fold of the WT group, the relative expression of western blot proteins increased synchronously; the increase in the number of immunohistochemically positive cells increased synchronously, and (5) plasma inflammatory factors were significantly elevated in db\/db mice: IL\u20106 \u21913.81\u2010fold, TNF\u2010\u03b1 \u21914.23\u2010fold, NF\u2010\u03baB \u21913.56\u2010fold. This study reveals for the first time the molecular mechanism by which diabetes drives cerebral small vessel disease (CSVD) through the spatiotemporal\u2010dependent activation of the necrotic apoptotic pathway (RIP1\/RIP3\/MLKL), and targeting the necrotic apoptotic pathway may serve as a potential therapeutic strategy for diabetes\u2010associated cognitive deficits by concurrently protecting the blood\u2013brain barrier and suppressing neuroinflammation.<\/jats:p>","DOI":"10.1096\/fj.202500772r","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T14:19:52Z","timestamp":1758550792000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Role of Necroptosis and Neuroinflammation in\n                    <scp>CSVD<\/scp>\n                    \u2010Associated Cognitive Decline in db\/db Mice"],"prefix":"10.1096","volume":"39","author":[{"given":"Dan\u2010Qiong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Geriatric Medicine Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital  Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital  Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology The Second Hospital of Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Meng","family":"Gu","sequence":"additional","affiliation":[{"name":"Department 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