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Conference Paper: Perturbation of endoplasmic reticulum and mitochondria rather than reduced activity of mTOR trigger autophagy in neurons exposed to low molecular weight beta-Amyloid peptide

TitlePerturbation of endoplasmic reticulum and mitochondria rather than reduced activity of mTOR trigger autophagy in neurons exposed to low molecular weight beta-Amyloid peptide
Authors
KeywordsAlzheimer’s disease
Autophagy
Beta amyloid
Issue Date2010
PublisherThe Society for Neuroscience.
Citation
The 40th Annual Meeting of the Society for Neuroscience (SfN 2010), San Diego, CA., 13-17 November 2010. How to Cite?
AbstractProgressive neurodegeneration is the key problem in Alzheimer’s disease (AD). Different modes of neurodegeneration including autophagy and apoptosis have been shown in AD. However, how autophagy is induced and how autophagy is transformed into apoptosis is still elusive. Our previous study has demonstrated that neurons exposed to low molecular weight β-amyloid peptide (LMW-Aβ) induce collapse of the endoplasmic reticulum (ER). Therefore, we hypothesize that disruption of intracellular organelles rather than inhibition of autophagic signaling pathway trigger the initial formation of autophagic vacuoles. Primary cultures of rat cortical neurons were prepared and transfected with LC3-, DFCP-1-, ER retention signal (KDEL)-, and mitochondrial retention signal expressing plasmids. Neurons were treated with LMW-Aβ. Protein lysates were collected afterwards for Western-blot analysis. Autophagosome, omegosome, lysosome and the morphology of the ER and mitochondria were examined by confocal microscopy. Quantitative data was analyzed by one way analysis of variance followed by Student Newman Keul test according to the statistical program SigmaStat® (Jandel Scientific) to compare the level significance. A p-value less than 0.05 was regarded as significant, at *p<0.05. We demonstrated that LMW-Aβ induced autophagic vacuoles and omegosome formation which showed partial colocalization in cortical neurons. Aβ induced AMP-activated protein kinase (AMPK) but did not cause significant suppression on mTOR and its downstream target p70S6 kinase (p70S6K) simultaneously. On the other hand, LMW-Aβ caused morphological damages in both ER and mitochondria at early time points. Organelle damage coincided with up-regulations in autophagy and lysosomal machinery. Our results suggest that LMW-Aβ first confers its toxicity on the intracellular organelles by causing structural damages to initiate autophagy. Deregulated cellular metabolism due to mitochondrial damage activates AMPK, which suppresses mTOR at later time points to exert synergistic effects on autophagy regulation.
DescriptionPoster session 247 - Alzheimer's Disease: Abeta, Energy Metabolism, Cell Signaling, Autophagy
Ref. no. 247.14/H60
Persistent Identifierhttp://hdl.handle.net/10722/142622

 

DC FieldValueLanguage
dc.contributor.authorChang, RCCen_US
dc.contributor.authorZhang, YQen_US
dc.contributor.authorHung, CHLen_US
dc.contributor.authorCheung, YTen_US
dc.date.accessioned2011-10-28T02:53:24Z-
dc.date.available2011-10-28T02:53:24Z-
dc.date.issued2010en_US
dc.identifier.citationThe 40th Annual Meeting of the Society for Neuroscience (SfN 2010), San Diego, CA., 13-17 November 2010.en_US
dc.identifier.urihttp://hdl.handle.net/10722/142622-
dc.descriptionPoster session 247 - Alzheimer's Disease: Abeta, Energy Metabolism, Cell Signaling, Autophagy-
dc.descriptionRef. no. 247.14/H60-
dc.description.abstractProgressive neurodegeneration is the key problem in Alzheimer’s disease (AD). Different modes of neurodegeneration including autophagy and apoptosis have been shown in AD. However, how autophagy is induced and how autophagy is transformed into apoptosis is still elusive. Our previous study has demonstrated that neurons exposed to low molecular weight β-amyloid peptide (LMW-Aβ) induce collapse of the endoplasmic reticulum (ER). Therefore, we hypothesize that disruption of intracellular organelles rather than inhibition of autophagic signaling pathway trigger the initial formation of autophagic vacuoles. Primary cultures of rat cortical neurons were prepared and transfected with LC3-, DFCP-1-, ER retention signal (KDEL)-, and mitochondrial retention signal expressing plasmids. Neurons were treated with LMW-Aβ. Protein lysates were collected afterwards for Western-blot analysis. Autophagosome, omegosome, lysosome and the morphology of the ER and mitochondria were examined by confocal microscopy. Quantitative data was analyzed by one way analysis of variance followed by Student Newman Keul test according to the statistical program SigmaStat® (Jandel Scientific) to compare the level significance. A p-value less than 0.05 was regarded as significant, at *p<0.05. We demonstrated that LMW-Aβ induced autophagic vacuoles and omegosome formation which showed partial colocalization in cortical neurons. Aβ induced AMP-activated protein kinase (AMPK) but did not cause significant suppression on mTOR and its downstream target p70S6 kinase (p70S6K) simultaneously. On the other hand, LMW-Aβ caused morphological damages in both ER and mitochondria at early time points. Organelle damage coincided with up-regulations in autophagy and lysosomal machinery. Our results suggest that LMW-Aβ first confers its toxicity on the intracellular organelles by causing structural damages to initiate autophagy. Deregulated cellular metabolism due to mitochondrial damage activates AMPK, which suppresses mTOR at later time points to exert synergistic effects on autophagy regulation.-
dc.languageengen_US
dc.publisherThe Society for Neuroscience.-
dc.relation.ispartof40th Annual Meeting of the Society for Neuroscience, SfN 2010en_US
dc.subjectAlzheimer’s disease-
dc.subjectAutophagy-
dc.subjectBeta amyloid-
dc.titlePerturbation of endoplasmic reticulum and mitochondria rather than reduced activity of mTOR trigger autophagy in neurons exposed to low molecular weight beta-Amyloid peptideen_US
dc.typeConference_Paperen_US
dc.identifier.emailChang, RCC: rccchang@hkucc.hku.hken_US
dc.identifier.emailZhang, YQ: natzhang@HKUSUC.hku.hk-
dc.identifier.emailHung, CHL: chlhung@hku.hk-
dc.identifier.emailCheung, YT: esonar@gmail.com-
dc.identifier.authorityChang, RCC=rp00470en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros184448en_US
dc.publisher.placeUnited States-
dc.customcontrol.immutablesml 130715-

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