Role of Necroptosis and Neuroinflammation in CSVD ‐Associated Cognitive Decline in db/db Mice

作者：Dan‐Qiong Wang, Lei Wang, Ping Zhao, Yian Gu, Xiaoshuang Xia, Tao Li, Na An, Xin Li · 发表于：The FASEB Journal · 年份：2025 · DOI：10.1096/fj.202500772r · 被引用次数：5 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neurological Disease Mechanisms and Treatments、Advanced Glycation End Products research

Diabetes-related cerebral small-vessel 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-type C57BL/6 mice and leptin receptor-deficient db/db mice were categorized into six groups according to age (8-, 12-, and 16-week 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-brain barrier-associated proteins were detected by western blot and RT-qPCR (occludin, ZO-1, VEGFA) and necroptotic apoptotic pathway molecules (RIP1, RIP3, MLKL). Western blot and RT-qPCR were used to detect the protein and mRNA expression of blood-brain barrier-associated proteins (occludin, ZO-1, 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-6, IL-10, TNF-α, NF-κB) were quantified by ELISA. In db...