Idebenone Decreases A beta Pathology by Modulating RAGE/Caspase-3 Signaling and the A beta Degradation Enzyme NEP 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 A beta plaque number via multi-directional pathways in this model. Specifically, idebenone reduced the RAGE/caspase-3 signaling pathway and increased levels of the A beta degradation enzyme NEP and alpha-secretase ADAM17 in 5xFAD mice. Importantly, idebenone significantly suppressed tau kinase p-GSK3 beta(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.