Dataset Information

Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ 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 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.

SUBMITTER: Lee HJ

PROVIDER: S-EPMC8471964 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Lee Hyun-Ju HJ Jeong Ha-Ram HR Park Jin-Hee JH Hoe Hyang-Sook HS

Biology 20210919 9

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 th ...[more]

PMID: 34571815

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Project description:IntroductionErlotinib is an epidermal growth factor receptor (EGFR) inhibitor that is approved by the FDA to treat non-small cell lung cancer (NSCLC). Several membrane receptors, including EGFR, interact with amyloid β (Aβ), raising the possibility that erlotinib could have therapeutic effects on Alzheimer's disease (AD). However, the effects of erlotinib on Aβ/tau-related pathology and cognitive function in mouse models of AD and its mechanisms of action have not been examined in detail.MethodsTo investigate the effects of erlotinib on cognitive function and AD pathology, 3 to 6-month-old PS19 mice and 3 to 3.5-month-old 5xFAD mice and WT mice were injected with vehicle (5% DMSO + 10% PEG + 20% Tween80 + 65% D.W.) or erlotinib (20 mg/kg, i.p.) daily for 14 or 21 days. Then, behavioral tests, Golgi staining, immunofluorescence staining, western blotting ELISA, and real-time PCR were conducted.Results and discussionWe found that erlotinib significantly enhanced short-term spatial memory and dendritic spine formation in 6-month-old P301S tau transgenic (PS19) mice. Importantly, erlotinib administration reduced tau phosphorylation at Ser202/Thr205 (AT8) and Thr231 (AT180) and further aggregation of tau into paired helical fragments (PHFs) and neurofibrillary tangles (NFTs) in 3-month-old and/or 6-month-old PS19 mice by suppressing the expression of the tau kinase DYRK1A. Moreover, erlotinib treatment decreased astrogliosis in 6-month-old PS19 mice and reduced proinflammatory responses in primary astrocytes (PACs) from PS19 mice. In 3- to 3.5-month-old 5xFAD mice, erlotinib treatment improved short-term spatial memory and hippocampal dendritic spine number and diminished Aβ plaque deposition and tau hyperphosphorylation. Furthermore, erlotinib-treated 5xFAD mice exhibited significant downregulation of astrocyte activation, and treating PACs from 5xFAD mice with erlotinib markedly reduced cxcl10 (reactive astrocyte marker) and gbp2 (A1 astrocyte marker) mRNA levels and proinflammatory cytokine mRNA and protein levels. Taken together, our results suggest that erlotinib regulates tau/Aβ-induced AD pathology, cognitive function, and Aβ/tau-evoked astrogliosis and therefore could be a potent therapeutic drug for ameliorating AD symptoms.

Project description:BackgroundSepsis-induced liver dysfunction is believed to be an independent risk factor for multiple organ dysfunction and death. Idebenone (IDE), a synthetic analog of coenzyme Q10 (CoQ10), possesses an antioxidizing property. The present study aimed to investigate the efficacy of IDE on sepsis-induced liver injury and discuss its reaction mechanism in vivo and in vitro.MethodsTo establish an in vivo model of sepsis-induced liver injury, rats were treated with high-grade cecal ligation and puncture (CLP). Hematoxylin-eosin staining was applied to observe the liver pathological changes, and liver function was examined using alanine aminotransferase (ALT) and aspartate aminotransferase (AST) assay kits. Enzyme-linked immunosorbent assay (ELISA) kits were employed to assess the levels of inflammatory cytokines in serum and tissues. The activities of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were analyzed using MDA, SOD, and GSH-Px assay kits, respectively. The apoptosis of liver tissues was measured by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) staining, and western blot was employed to estimate apoptosis-related proteins. In vitro, 0.5 μg/mL lipopolysaccharide (LPS) was adopted to administrate primary hepatocytes. The expressions of receptor for advanced glycation end products (RAGE)/p38-related proteins were evaluated by western blot. Cell counting kit-8 (CCK-8) and dichloro-dihydro-fluorescein diacetate (DCFH-DA) assays were utilized to estimate cell viability and reactive oxygen species (ROS) content. Moreover, the transfection efficacy of overexpression (Ov)-RAGE in primary hepatocytes was tested by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot.ResultsIDE could improve liver function and reduce sepsis-induced pathological damage. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the serum and liver tissue of sepsis rats were suppressed by IDE. Additionally, IDE repressed the oxidative stress and apoptosis of liver tissues in sepsis-induced rats. IDE also inhibited RAGE/p38 signaling. Furthermore, IDE revived the decreased viability in LPS-induced hepatocytes concentration-dependently. After overexpressing RAGE, RAGE expression in hepatocytes was significantly elevated. Further functional experiments revealed that IDE attenuated cell viability injury, apoptosis, oxidative stress, and inflammatory damage in LPS-induced hepatocytes via RAGE/p38 signaling.ConclusionsIDE helped to protect against sepsis-induced liver injury via the regulation of RAGE/p38 signaling.

Dataset Information

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

Publications

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

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