miR-449a is involved in Alzheimer's disease pathology through targeted regulation of Navβ2

Alzheimer's disease (AD) progression from mild cognitive impairment (MCI) to dementia is insidious and necessitates a deep understanding of underlying molecular mechanisms for effective intervention. We investigated the roles of Navβ2 and its regulatory microRNA, miR-449a, in MCI and AD pathology using multiple mouse models. Our findings reveal dysregulated Navβ2 expression in MCI and AD mice, associated with synaptic abnormalities, disrupted amyloid precursor protein (APP) processing, and altered Nav1.1α expression. Importantly, miR-449a modulation influences synaptic function and cognition through Navβ2 regulation, with overexpression improving and inhibition exacerbating cognitive impairments. Co-transfection experiments demonstrate the mediating role of Navβ2 in miR-449a's effects on APP metabolism. Electrophysiological recordings further support the involvement of miR-449a and Navβ2 in cognitive regulation. We propose miR-449a and Navβ2 as potential therapeutic targets for AD, highlighting their intricate interplay in synaptic dysfunction and cognitive decline. These findings provide novel insights into the molecular mechanisms underlying synaptic dysfunction in AD and highlight Navβ2 and miR-449a as potential therapeutic targets for the treatment of cognitive impairment in AD. Further investigation of the Navβ2/miR-449a axis may lead to the development of targeted therapies aimed at preserving synaptic integrity and cognitive function in AD patients.