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Article

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

1
Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61 Cheomdan-ro, Dong-gu, Daegu 41068, Korea
2
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, Korea
*
Author to whom correspondence should be addressed.
Academic Editors: Katsuya Iuchi, Young-Ho Lee and Masaki Okumura
Biology 2021, 10(9), 938; https://doi.org/10.3390/biology10090938
Received: 30 August 2021 / Revised: 14 September 2021 / Accepted: 17 September 2021 / Published: 19 September 2021
(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)
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.
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-GSK3βY216 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. View Full-Text
Keywords: Alzheimer’s disease; idebenone; Aβ; ADAM17; NEP; 5xFAD Alzheimer’s disease; idebenone; ; ADAM17; NEP; 5xFAD
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MDPI and ACS Style

Lee, H.-j.; Jeong, H.-R.; Park, J.-H.; Hoe, H.-S. Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD. Biology 2021, 10, 938. https://doi.org/10.3390/biology10090938

AMA Style

Lee H-j, Jeong H-R, Park J-H, Hoe H-S. Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD. Biology. 2021; 10(9):938. https://doi.org/10.3390/biology10090938

Chicago/Turabian Style

Lee, Hyun-ju, Ha-Ram Jeong, Jin-Hee Park, and Hyang-Sook Hoe. 2021. "Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD" Biology 10, no. 9: 938. https://doi.org/10.3390/biology10090938

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