MiR-144 Regulates Cognitive Dysfunction via NLRP3 Inflammasome and FoxO1/AdipoR Pathway in T2DM Mice

Type 2 diabetes mellitus (T2DM) is closely related to cognitive impairment, with underlying pathological mechanisms including chronic inflammation, synaptic dysfunction, and microglial dysregulation. Although microRNA-144 (miR-144) has been implicated in these processes, its precise role and molecular mechanisms remain unclear. T2DM mouse models were established using a high-fat diet combined with low-dose streptozotocin, and microglia-specific miR-144 intervention was achieved in the hippocampus via bilateral injection of adeno-associated virus. Cognitive function was assessed using the novel object recognition and Morris water maze tests, while synaptic plasticity, microglial phenotype, neuroinflammation, and Tau pathology were evaluated by immunofluorescence, Western blot, Golgi staining, transmission electron microscopy, and electrophysiology. Our results showed that overexpression of miR-144 mimicked the pathological state of T2DM, leading to impaired learning and memory, neuronal dysfunction, reduced expression of synaptic proteins, and decreased dendritic spine density. Additionally, miR-144 overexpression significantly suppressed FoxO1 and AdipoR1/AdipoR2 expression while inducing microglial M1 polarization, activating downstream NLRP3-mediated neuroinflammatory responses, and increasing Tau phosphorylation. Conversely, miR-144 knockdown effectively ameliorated these pathological changes and provided neuroprotection. These findings suggest that miR-144 could serve as a promising biomarker and therapeutic target for T2DM-related cognitive impairment. This study offers novel insights into the underlying mechanisms of T2DM-related cognitive impairment and provides an experimental foundation for exploring miR-144-based intervention strategies.