The Inflammasome-miR Axis in Alzheimer's Disease and Chronic Pain: Molecular Mechanisms and Therapeutic Opportunities.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and chronic neuroinflammation. Mounting evidence suggests that inflammasome activation plays a pivotal role in the onset and progression of AD by promoting neuronal damage, Tau pathology, and amyloid-β (Aβ) accumulation. Among the various inflammasome types expressed in the central nervous system (CNS), NLRP3 has received particular attention due to its strong association with both AD and pain-related neuroinflammation. Chronic pain, frequently observed in older adults and individuals with dementia, shares overlapping inflammatory mechanisms with AD, including glial activation and cytokine dysregulation. The inflammasome-microRNA (miR) axis has recently emerged as a key regulatory pathway modulating these neuroinflammatory responses. Specific inflammation-associated miRs, such as miR-22, miR-34a, miR-146a, miR-155, and miR-223, influence innate immune signaling and critically affect both neuronal homeostasis and pain sensitization. Emerging evidence also implicates dysfunction of the locus coeruleus-noradrenergic (LC-NE) system-an early target of AD pathology-in amplifying neuroinflammation and pain sensitivity, partly through interactions with dysregulated miRs. While previous studies have addressed the roles of inflamma-miRs in AD or chronic pain individually, this review uniquely examines their interconnected roles-highlighting how dysregulated miR expression and inflammasome activation may converge to drive persistent neuroinflammation across both conditions. By elucidating shared molecular pathways, we propose that targeting the inflammasome-miR axis may offer dual therapeutic potential: slowing AD progression while addressing pain-related neural dysfunction. As the prevalence of AD rises, such integrated insights are essential for the development of more precise, mechanism-based interventions.