Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5508706 | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | 2016 | 15 Pages |
Abstract
Mitochondrial dysfunction is known as one of causative factors in Alzheimer's disease (AD), inducing neuronal cell death. Mitochondria regulate their functions through changing their morphology. The present work was undertaken to investigate whether Amyloid β (Aβ) affects mitochondrial morphology in neuronal cells to induce apoptosis. Aβ treatment induced not only the fragmentation of mitochondria but also neuronal apoptosis in association with an increase in caspase-9 and -3 activity. Calcium influx induced by Aβ up-regulated the activation of Akt through CaMKII resulting in changes to the phosphorylation level of Drp1 in a time-dependent manner. Translocation of Drp1 from the cytosol to mitochondria was blocked by CB-124005 (an Akt inhibitor). Recruitment of Drp1 to mitochondria led to ROS generation and mitochondrial fission, accompanied by dysfunction of mitochondria such as loss of membrane potential and ATP production. ROS generation and mitochondrial dysfunction by Aβ were attenuated when treated with Mdivi-1, a selective Drp1 inhibitor. Furthermore, the sustained Akt activation induced not only the fragmentation of mitochondria but also the activation of mTOR, eventually suppressing autophagy. Inhibition of autophagic clearance of Aβ led to increased ROS levels and aggravating mitochondrial defects, which were blocked by Rapamycin (an mTOR inhibitor). In conclusion, sustained phosphorylation of Akt by Aβ directly activates Drp1 and inhibits autophagy through the mTOR pathway. Together, these changes elicit abundant mitochondrial fragmentation resulting in ROS-mediated neuronal apoptosis.
Keywords
ROCK1N-acetyl-l-cysteineDulbecco Modified Eagle MediumCaMKIIPKCδERKHFIPmTORAβNACNMDARNGScytosine arabinosideL-VGCCFITCFis1FBSDMEMPBSCDKDrp11,1,1,3,3,3-hexafluoro-2-propanolopa1Adenosine TriphosphateATPamyloid βAktAlzheimer's diseaseAraCelectron transport chainCAMfetal bovine serumnormal goat serumfluorescein isothiocyanatephosphate buffered solutionmammalian target of rapamycinETcDynamin-related proteinprotein kinase BCalmodulinL-type voltage-gated calcium channelextracellular signal-regulated kinasecyclin dependent kinaseN-methyl-d-aspartate receptor
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Authors
Dah Ihm Kim, Ki Hoon Lee, Amr Ahmed Gabr, Gee Euhn Choi, Jun Sung Kim, So Hee Ko, Ho Jae Han,