AgomiR-31-5p ameliorates diabetes-associated cognitive impairment by suppressing hippocampal neuroinflammation via RAGE-associated signaling.

Abstract

Diabetes-associated cognitive impairment is closely linked to hippocampal neuroinflammation, but effective treatments remain limited. This study investigated the protective effects of agomiR-31-5p against cognitive dysfunction and neuroinflammatory injury in db/db mice. Male db/db mice received agomiR-31-5p via tail-vein injection, followed by assessments of cognition, hippocampal microglial activation, synaptic integrity, apoptosis, and inflammatory signaling. AgomiR negative controls were included in the corresponding molecular and cellular experiments. AgomiR-31-5p improved cognitive performance compared with vehicle treatment and attenuated microglial activation, as evidenced by reduced IBA1 and CD68 immunoreactivity, partial normalization of microglial morphology, decreased iNOS expression, and increased IL-10 expression. It also restored PSD95 and SYN expression, reduced the spatial association between microglial and PSD95 signals, and ameliorated apoptosis-related alterations. Molecular docking predicted a potential interaction between agomiR-31-5p and RAGE. In vivo, agomiR-31-5p reduced RAGE expression, p38/ERK/NF-κB signaling activation, and hippocampal TNF-α, IL-6, and IL-1β levels. In high glucose-exposed primary microglia, agomiR-31-5p suppressed inflammatory activation and RAGE/NF-κB signaling. RAGE overexpression partially reversed these effects, supporting the functional involvement of RAGE-associated signaling without establishing RAGE as a direct agomiR-31-5p target. Collectively, agomiR-31-5p may alleviate diabetes-associated cognitive impairment by attenuating microglia-mediated neuroinflammation, preserving synaptic integrity, reducing apoptosis-related injury, and modulating RAGE-associated signaling.