Repurposing MitoQ10 as a Therapeutic for Established Alzheimer's Disease Pathology.

Abstract

Alzheimer's Disease (AD) is characterized by progressive amyloid accumulation, neuroinflammation, and neuronal loss, yet therapies targeting amyloid alone provide limited clinical benefit. Here, we evaluated whether pharmacological targeting of mitochondrial redox dysfunction using MitoQ10 (MitoQ), a mitochondria-targeted antioxidant, could modify AD pathology and behavioral deficits in symptomatic 5XFAD mice. Four-month-old 5XFAD mice received oral MitoQ for four months, and behavioral, histological, and biochemical analyses were performed at eight months of age. MitoQ administration significantly improved novelty-related exploration, attenuated hyper-locomotor activity, and broadly suppressed amyloid pathology, including pan-Aβ, oligomeric Aβ species, fibrillar plaques, and mature amyloid deposits across the cortex, hippocampus, thalamus, and amygdala. MitoQ also attenuated astrocyte and microglial reactivation, reduced pathological pTau622, and preserved neuronal integrity. Restoration of mitochondrial homeostasis was reflected by increased PDH-positive mitochondrial particle area, reduced oxidative DNA damage, and normalization of mitochondrial clearance via restoration of mitophagy-associated quality-control markers. Collectively, these findings show that MitoQ administration was associated with improvement in mitochondrial redox- and quality-control-related indices, accompanied by reductions in amyloid burden, gliosis, and neuronal injury in animals with established AD pathology. These findings support mitochondrial redox homeostasis as a therapeutically relevant target that may influence multiple pathological features of AD and provide a preclinical rationale for further evaluation of MitoQ as a potential therapeutic strategy for AD. Given that MitoQ has been evaluated in clinical studies in other conditions, the present preclinical findings support further investigation of its translational potential in AD; however, its safety and efficacy in individuals with AD require direct clinical evaluation.