Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer＇s disease. Here, we found that indirubin-3′-monoxime improved th...Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer＇s disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SHSY5 Y cells exposed to amyloid-beta 25–35（Aβ25–35）, and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β（GSK-3β）. Our results suggest that indirubin-3′-monoxime reduced Aβ25–35-induced apoptosis by suppressing tau hyperphosphorylation via a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer＇s disease.展开更多
Alzheimer's disease(AD)is an irreversible neurodegenerative disorder,which is pathologically characterized by the deposits of β-amyloid(Aβ),and plays an important role in neuronal death.Indirubin-30-monoxime(I3M...Alzheimer's disease(AD)is an irreversible neurodegenerative disorder,which is pathologically characterized by the deposits of β-amyloid(Aβ),and plays an important role in neuronal death.Indirubin-30-monoxime(I3M)showed neuroprotective effects against Aβ-induced neuronal apoptosis.However,the use of I3M in AD treatment is limited due to its low bioavailability.Herein,PLGA-PEG nanoparticles were synthesized for I3M loading.I3M could release sustainedly sustain release from the I3M-loaded PLGA-PEG nanoparticles(PLGA-PEG-I3M NPs)without obvious burst release.What's more,the PLGA-PEG-I3M NPs could significantly promote the uptake of I3M by PC12 cells through nanoparticle-mediated transport,and improve the efficacy of I3M on the inhibition of Aβfibrillization and oligomerization as well as the neuroprotective activity of I3M on Aβoligomers-induced neuronal death.Thus,the PLGA-PEG-I3M NPs may be a promising platform for AD therapy.展开更多
基金supported by the Nanjing Medical Science and Technique Development Foundation of China,No.QRX11199a grant from the Nanjing Science and Technology Commission Project of China,No.201303010a grant from the Health Research Project in Nanjing City of China,No.YKK14101
文摘Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer＇s disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SHSY5 Y cells exposed to amyloid-beta 25–35（Aβ25–35）, and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β（GSK-3β）. Our results suggest that indirubin-3′-monoxime reduced Aβ25–35-induced apoptosis by suppressing tau hyperphosphorylation via a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer＇s disease.
基金Thanks for the funding by National Natural Science Foundation of China(Grant No.81870853)Natural Science Foundation of Zhejiang Province(Grant No.LY21H090002)+6 种基金Natural Science Foundation of Ningbo(Grant No.2018A610313)Natural Science Foundation of Guangdong(Grant No.2019A1515011750,2021A1515010720)Major program of Ningbo Science and Technology Innovation 2025(Grant No.2019B1006)Ningbo municipal innovation team of life science and health(Grant No.2015C110026)Basic scientific research operating expenses of provincial universities(Grant No.SJLY2021002)Science and Technology Innovation Commission of Shenzhen(Grant No.ZDSYS20200811142600003,JCYJ20180507183036060,JCYJ20190806161409092,JCYJ20210324103012033,JCYJ20180228162928828)LiDakSum Marine Biopharmaceutical Development Fund,the K.C.Wong Magna Fund in Ningbo University and the Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province.
文摘Alzheimer's disease(AD)is an irreversible neurodegenerative disorder,which is pathologically characterized by the deposits of β-amyloid(Aβ),and plays an important role in neuronal death.Indirubin-30-monoxime(I3M)showed neuroprotective effects against Aβ-induced neuronal apoptosis.However,the use of I3M in AD treatment is limited due to its low bioavailability.Herein,PLGA-PEG nanoparticles were synthesized for I3M loading.I3M could release sustainedly sustain release from the I3M-loaded PLGA-PEG nanoparticles(PLGA-PEG-I3M NPs)without obvious burst release.What's more,the PLGA-PEG-I3M NPs could significantly promote the uptake of I3M by PC12 cells through nanoparticle-mediated transport,and improve the efficacy of I3M on the inhibition of Aβfibrillization and oligomerization as well as the neuroprotective activity of I3M on Aβoligomers-induced neuronal death.Thus,the PLGA-PEG-I3M NPs may be a promising platform for AD therapy.
