Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD

SIMPLE SUMMARY: The present study reveals that the FDA-approved drug idebenone has therapeutic effects on the pathology of Alzheimer’s disease (AD) in a mouse model. In particular, idebenone regulates pathological progression associated with Aβ by downregulating the non-amyloidogenic pathway, inhibiting RAGE/caspase-3 signaling, and enhancing Aβ catabolism. In addition, idebenone modulates tauopathy by reducing levels of the tau kinase p-GSK3β, thereby suppressing tau hyperphosphorylation at Thr231. These data suggest that idebenone modulates Aβ and tau pathology in a mouse model of AD. ABSTRACT: The coenzyme Q10 analogue idebenone is an FDA-approved antioxidant that can cross the blood–brain barrier (BBB). The effects of idebenone on the pathology of Alzheimer’s disease (AD) and the underlying molecular mechanisms have not been comprehensively investigated. Here, we examined the impact of idebenone treatment on AD pathology in 5xFAD mice, a model of AD. Idebenone significantly downregulated Aβ plaque number via multi-directional pathways in this model. Specifically, idebenone reduced the RAGE/caspase-3 signaling pathway and increased levels of the Aβ degradation enzyme NEP and α-secretase ADAM17 in 5xFAD mice. Importantly, idebenone significantly suppressed tau kinase p-GSK3β(Y216) levels, thereby inhibiting tau hyperphosphorylation at Thr231 and total tau levels in 5xFAD mice. Taken together, the present study indicates that idebenone modulates amyloidopathy and tauopathy in 5xFAD mice, suggesting therapeutic potential for AD.