miR-449a modulates Alzheimer’s disease pathology through regulation of Navβ2

Progression of Alzheimer’s disease (AD) from mild cognitive impairment (MCI) to dementia occurs gradually and remains mechanistically unresolved, limiting development of effective interventions. This study investigated the contribution of Navβ2 and its upstream regulatory microRNA, miR-449a, to MCI- and AD-associated neuropathology in multiple mouse models. Results revealed that Navβ2 expression was dysregulated in MCI and AD mice, accompanied by synaptic abnormalities, aberrant amyloid precursor protein (APP) processing, and disrupted Nav1.1α expression. Importantly, manipulation of miR-449a markedly influenced synaptic function and cognition through regulation of Navβ2, with miR-449a overexpression alleviating and miR-449a inhibition exacerbating cognitive impairment. Co-transfection assays further demonstrated that the effects of miR-449a on APP metabolism were mediated by Navβ2. Electrophysiological analyses provided additional evidence that the miR-449a/Navβ2 axis participates in regulation of cognitive function. Together, these findings provide new mechanistic insight into synaptic dysfunction and cognitive decline in AD and identify the miR-449a/Navβ2 axis as a candidate therapeutic target for cognitive impairment. Further investigation of the miR-449a/Navβ2 axis may facilitate development of targeted strategies to preserve synaptic integrity and cognitive function during AD progression.