Idebenone protects mitochondrial function against amyloid beta toxicity in primary cultured cortical neurons

Abstract

Mitochondrial dysfunction has been repeatedly identified to be hallmark brain pathology underlying neuronal stress in Alzheimer’s disease. As a result, mitochondrial medicine for the treatment of Alzheimer’s disease has received increasing recognition. Idebenone (IDB) is a synthetic analog of Coenzyme Q10 (CoQ10) carrying antioxidizing property. Previous clinical trials reported a conflicting disease-modifying effect of IDB on Alzheimer’s disease patients. However, whether IDB is preventive against amyloid beta (Aβ)-induced mitochondrial and neuronal stress has not been comprehensively investigated. In this study, we adopted an in-vitro setting by using primary cultured cortical neurons for the test. Neurons were pretreated with IDB prior to Aβ exposure. IDB pretreatment significant prevented neurons from Aβ-induced collapse of mitochondrial bioenergetics and perturbations of the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling. Importantly, the treatment of IDB alone demonstrated an indiscernible side effect on the measured mitochondrial function, PKA/CREB signaling and neuronal viability. Therefore, our findings in together show a preventive effect of IDB against Aβ-mediated mitochondrial and neuronal injury. The use of IDB may hold potential to reduce the risk of Alzheimer’s disease as a preventive strategy.

Facile Solvent-Free Preparation of Antioxidant Idebenone-Loaded Nanoparticles for Efficient Wound Healing

“…Cells were seeded in 96-well plates at a density of 10,000 cells per well. After 24 h of incubation, the cells were treated with various concentrations of IB@NPs (250 nM to 5 µM) and incubated for 24 h at 37 °C [ 35 , 36 ]. Subsequently, the medium was replaced with MTT solution at a concentration of 1 mg/mL, fresh medium was added to each well, and incubation continued for 3 h. The medium was then removed, and DMSO-d6 was added to dissolve the purple formazan dye crystals.…”

The Role of a Pathological Interaction between β-amyloid and Mitochondria in the Occurrence and Development of Alzheimer’s Disease

“…Так, антиоксидантом, одобренным FDA, является идебенон -аналог коэнзима Q10, способный проходить через гематоэнцефалический барьер. Идебенон ингибирует Aβ-индуцированное образование АФК и митохондриальную дисфункцию [217]. Показано, что введение идебенона значительно снижает накопление отложений Aβ у мышей 5xFAD за счет повышения уровней α-секретазы ADAM17 и NEP, а также подавляет передачу сигналов RAGE/каспазы-3 [218].…”

“…An example is idebenone, a coenzyme Q10 analogue that can pass through the BBB, which is an FDA-approved antioxidant. Idebenone inhibits Aβ-induced ROS production and mitochondrial dysfunction [ 217 ]. Idebenone administration significantly reduces Aβ deposition in 5xFAD mice by increasing the levels of α-secretase ADAM17 and NEP; it also inhibits the RAGE/caspase-3 signaling pathway [ 218 ].…”

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

“…The FDA-approved drug idebenone is a coenzyme Q10 analogue that can cross the BBB [ 13 ]. Idebenone has been shown to restore Aβ-induced mitochondrial dysfunction and neural toxicity in primary cortical neurons [ 14 ]. In addition, idebenone improves hippocampal-dependent spatial memory function in Aβ-injected rats and mice by promoting Aβ-degrading enzyme levels and antioxidant activity [ 14 , 15 ].…”

“…Idebenone has been shown to restore Aβ-induced mitochondrial dysfunction and neural toxicity in primary cortical neurons [ 14 ]. In addition, idebenone improves hippocampal-dependent spatial memory function in Aβ-injected rats and mice by promoting Aβ-degrading enzyme levels and antioxidant activity [ 14 , 15 ]. However, whether idebenone affects Aβ plaque deposition and its underlying molecular mechanisms has not been fully investigated in a genetically modified mouse model of AD.…”