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Conference Paper: Disruptions of endoplasmic reticulum and mitochondria prime mTOR suppression in low molecular weight Aβ-induced autophagy

TitleDisruptions of endoplasmic reticulum and mitochondria prime mTOR suppression in low molecular weight Aβ-induced autophagy
Authors
KeywordsMedical sciences
Psychiatry and neurology gerontology and geriatrics
Issue Date2010
PublisherElsevier Inc. The Journal's web site is located at http://www.alzheimersanddementia.org/
Citation
The 2010 Alzheimer's Association International Conference on Alzheimer's Disease, Honolulu, HI., 10-15 July 2010. In Alzheimer's & Dementia, 2010, v. 6 n. 4, suppl. 1, p. S243, abstract no. P1-239 How to Cite?
Abstract
BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder which pathological hallmarks associate with the deposition of insoluble beta-amyloid (Aβ) plaques in various regions of the brain. Reports suggested that various soluble Aβ species can induce neurotoxicity and are capable in inducing autophagy, the type II programmed cell death, with elusive mechanism of activation. METHODS: Primary cultures of rat embryonic cortical neurons were prepared and transfected with LC3-, DFCP-1-, endoplasmic reticulum (ER) retention signal (KDEL)-, and mitochondrial retention signal expressing plasmids. Neurons were treated with low molecular weight (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 (ANOVA) 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. RESULTS: In the present study, we demonstrated that low molecular weight Aβ induced autophagic vacuole 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 p70 S6 kinase (p70S6K) simultaneously. On the other hand, low MW Aβ caused morphological damages in both ER and mitochondria at early time points. Organelle damage coincided with up-regulations in autophagy and lysosomal machinery. CONCLUSIONS: Our results suggest that low MW Aβ first confers its toxicity on the intracellular organelles by causing structural damages to initiate autophagy. Dysregulated cellular metabolism due to mitochondrial damage activates AMPK, which suppresses mTOR at later time points to exert synergistic effects on autophagy regulation.
DescriptionPoster Presentations: P1-239
Persistent Identifierhttp://hdl.handle.net/10722/142627
ISSN
2013 Impact Factor: 17.472

 

DC FieldValueLanguage
dc.contributor.authorChang, RCCen_US
dc.contributor.authorCheung, YTen_US
dc.contributor.authorZhang, NQen_US
dc.contributor.authorHung, CHLen_US
dc.contributor.authorLai, CSWen_US
dc.contributor.authorYu, MSen_US
dc.date.accessioned2011-10-28T02:53:29Z-
dc.date.available2011-10-28T02:53:29Z-
dc.date.issued2010en_US
dc.identifier.citationThe 2010 Alzheimer's Association International Conference on Alzheimer's Disease, Honolulu, HI., 10-15 July 2010. In Alzheimer's & Dementia, 2010, v. 6 n. 4, suppl. 1, p. S243, abstract no. P1-239en_US
dc.identifier.issn1552-5260-
dc.identifier.urihttp://hdl.handle.net/10722/142627-
dc.descriptionPoster Presentations: P1-239-
dc.description.abstractBACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder which pathological hallmarks associate with the deposition of insoluble beta-amyloid (Aβ) plaques in various regions of the brain. Reports suggested that various soluble Aβ species can induce neurotoxicity and are capable in inducing autophagy, the type II programmed cell death, with elusive mechanism of activation. METHODS: Primary cultures of rat embryonic cortical neurons were prepared and transfected with LC3-, DFCP-1-, endoplasmic reticulum (ER) retention signal (KDEL)-, and mitochondrial retention signal expressing plasmids. Neurons were treated with low molecular weight (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 (ANOVA) 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. RESULTS: In the present study, we demonstrated that low molecular weight Aβ induced autophagic vacuole 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 p70 S6 kinase (p70S6K) simultaneously. On the other hand, low MW Aβ caused morphological damages in both ER and mitochondria at early time points. Organelle damage coincided with up-regulations in autophagy and lysosomal machinery. CONCLUSIONS: Our results suggest that low MW Aβ first confers its toxicity on the intracellular organelles by causing structural damages to initiate autophagy. Dysregulated 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.publisherElsevier Inc. The Journal's web site is located at http://www.alzheimersanddementia.org/-
dc.relation.ispartofAlzheimer's & Dementiaen_US
dc.subjectMedical sciences-
dc.subjectPsychiatry and neurology gerontology and geriatrics-
dc.titleDisruptions of endoplasmic reticulum and mitochondria prime mTOR suppression in low molecular weight Aβ-induced autophagyen_US
dc.typeConference_Paperen_US
dc.identifier.emailChang, RCC: rccchang@hkucc.hku.hken_US
dc.identifier.emailCheung, YT: esonar@gmail.comen_US
dc.identifier.emailHung, CHL: chlhung@hku.hk-
dc.identifier.emailLai, CSW: coralai@graduate.hku.hk-
dc.identifier.emailYu, MS: msyu@HKUCC.hku.hk-
dc.identifier.authorityChang, RCC=rp00470en_US
dc.identifier.hkuros181093en_US
dc.identifier.hkuros184455-
dc.identifier.volume6en_US
dc.identifier.issue4, suppl. 1en_US
dc.identifier.spageS243en_US
dc.identifier.epageS243en_US
dc.publisher.placeUnited States-

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