The overexpression of miR-146a in hippocampal microglia via IRAK1/TRAF6/NF-κB pathway improves cognitive function in diabetic mice

• Published in: Experimental neurology Vol. 391; p. 115291
• Main Authors: Zhang, Jingyu, Lin, Xiaoyun, Huang, Qing, Fu, Zhang, Huang, Yihuan, Chen, Zhiqing, Li, Ningning, Lin, Xiahong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2025
• Subjects: Animals; Cognition - physiology; Cognitive dysfunction; Cognitive Dysfunction - metabolism; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - psychology; Diabetic encephalopathy; Hippocampus - metabolism; Interleukin-1 Receptor-Associated Kinases - biosynthesis; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - metabolism; Male; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - metabolism; miR-146a; Neuroimmune; NF-kappa B - biosynthesis; NF-kappa B - metabolism; Signal Transduction - physiology; TNF Receptor-Associated Factor 6 - biosynthesis; TNF Receptor-Associated Factor 6 - metabolism; miR-146a; Diabetic encephalopathy; Neuroimmune; Cognitive dysfunction; Microglia
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2025.115291

Diabetic encephalopathy (DEP), a central nervous system complication of diabetes, is primarily characterized by cognitive dysfunction. Despite its high prevalence and significant risks, the pathogenesis remains poorly understood. This study investigates the effects and mechanisms of miR-146a on cognitive function in DEP mice. Type 2 diabetic mice models were established by feeding a high-fat diet and administering a low-dose of streptozotocin. And the Morris water maze test was conducted to assess the learning and memory. The adeno-associated virus was delivered into hippocampus by stereotactic injection to overexpress miR-146a in microglia. The mRNA and protein expression levels were determined by quantitative real-time polymerase chain reaction, immunofluorescence, Western blot, and enzyme-linked immunosorbent assay. DEP mice exhibited significantly reduced miR-146a expression in hippocampal microglia. This reduction was associated with elevated IRAK1, TRAF6, and NF-κB expression, increased markers of pro-inflammatory microglial phenotypes (CD86 and iNOS), and decreased markers of anti-inflammatory phenotypes (Arg-1 and CD206). Pro-inflammatory cytokines TNF-α and IL-6 were elevated, while anti-inflammatory IL-10 was reduced. Eventually, neuronal apoptosis and cognitive dysfunction were evident. Overexpression of miR-146a in hippocampal microglia reversed these molecular and phenotypic abnormalities, decreased neuronal apoptosis, and significantly improved cognitive performance in diabetic mice. Downregulation of miR-146a in hippocampal microglia disrupts immune homeostasis through the IRAK1/TRAF6/NF-κB pathway, contributing to DEP. Targeted overexpression of miR-146a restores immune homeostasis, reduces neuronal apoptosis, and ameliorates cognitive impairment. [Display omitted] •Diabetic encephalopathy inhibited the expression of miR-146a in microglia.•The miR-146a-depleted microglia expressed a large number of pro-inflammatory factors via IRAK1/TRAF6/NF-κB signaling pathway.•Overexpression of miR-146a in microglia inhibited IRAK1/TRAF6/NF-κB signaling pathway.•Overexpression of miR-146a significantly improved cognitive dysfunction caused by diabetes.