Dexmedetomidine as a potential neuroprotective agent against Alzheimer’s disease: molecular mechanisms and therapeutic perspectives

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by extracellular deposition of amyloid-β (Aβ), intracellular hyperphosphorylation of microtubule-associated protein tau and chronic neuroinflammation. At present, effective disease-modifying therapies for AD remain limited. Dexmedetomidine (Dex), a highly selective α 2 -adrenergic receptor agonist, has been reported in recent years to exert significant neuroprotective effects. Accumulating evidence indicates that Dex may ameliorate AD pathology through multiple mechanisms. In terms of Aβ metabolism, Dex reduces Aβ production by downregulating β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression. With respect to tau pathology, Dex may counteract abnormal tau hyperphosphorylation in AD-related models, although relatively high experimental doses have also been associated with increased tau phosphorylation. Regarding immune regulation, Dex attenuates neuroinflammatory signaling by inhibiting NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and related pro-inflammatory pathways. In addition, Dex modulates neurotrophic support, ferroptosis, autophagic flux, and synaptic homeostasis. These multitarget effects have been observed across heterogeneous preclinical models and dose ranges; however, an AD-specific therapeutic window and long-term safety profile remain to be established. This narrative review synthesizes the available preclinical evidence on the multitarget actions of Dex in AD-related models and critically evaluates dose dependence, pharmacokinetic and safety considerations, and current translational limitations.