MiR-144 regulates cognitive dysfunction via NLRP3 inflammasome and FoxO1/AdipoR pathway in T2DM mice

Background Type 2 diabetes mellitus (T2DM) is closely associated with cognitive impairment, with underlying pathological mechanisms including chronic inflammation, insulin resistance, and neuronal injury. Recent research indicates that microRNA-144 (miR-144) plays a critical role in these processes, though its exact mechanism remains unclear. Given the critical role of microglia in neuroinflammation and synaptic homeostasis, we investigated whether miR-144 mediates T2DM-related cognitive impairment by modulating microglial function through the Fork-head Box O1 (FoxO1)/AdipoR signaling pathway and activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome. Methods Microglia-specific T2DM mouse models were established using Cx3cr1-Cre mice subjected to a high-fat diet combined with low-dose streptozotocin administration. Microglia-selective overexpression or knockdown of miR-144 was achieved via stereotactic hippocampal injection of adeno-associated virus (AAV). Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic function and plasticity were assessed by electrophysiological recordings (mEPSCs/mIPSCs and AMPAR/NMDAR-EPSCs), ultrastructural analyses (Golgi staining and transmission electron microscopy), and molecular assays including Western blotting and immunofluorescence. Expression levels of synaptic proteins, Tau phosphorylation, FoxO1, AdipoR1/2, NLRP3 inflammasome components, and inflammatory cytokines were systematically analyzed. Results T2DM mice exhibited significant cognitive deficits accompanied by synaptic dysfunction, increased Tau phosphorylation, and enhanced neuroinflammatory responses. Notably, microglial overexpression of miR-144 recapitulated key pathological features of T2DM, including impaired learning and memory, disrupted synaptic transmission, reduced synaptic protein expression, decreased dendritic spine density, and elevated Tau phosphorylation. Additionally, miR-144 overexpression significantly suppressed FoxO1 and AdipoR1/AdipoR2 expression, leading to activation of the NLRP3 inflammasome and subsequent amplification of neuroinflammation. In contrast, microglial knockdown of miR-144 markedly alleviated cognitive impairment, restored synaptic integrity, suppressed Tau hyperphosphorylation, and attenuated neuroinflammatory signaling, thereby exerting robust neuroprotective effects. Conclusion This study identifies miR-144 as a pivotal regulator of T2DM-related cognitive dysfunction. miR-144 mediates microglial-driven neuroinflammation and synaptic impairment through suppression of the FoxO1/AdipoR signaling pathway and activation of the NLRP3 inflammasome. These findings highlight miR-144 as a potential biomarker and therapeutic target for preventing or treating cognitive impairment associated with T2DM.