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Article: Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis

TitleEndoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis
Authors
KeywordsAlzheimer's disease
ER stress
okadaic acid
tau phosphorylation
thapsigargin
Issue Date2012
PublisherI O S Press. The Journal's web site is located at http://www.iospress.nl/html/13872877.php
Citation
Journal Of Alzheimer's Disease, 2012, v. 28 n. 4, p. 839-854 How to Cite?
Abstract
Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration. © 2012 - IOS Press and the authors. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/146845
ISSN
2013 Impact Factor: 3.612
2013 SCImago Journal Rankings: 1.702
ISI Accession Number ID
Funding AgencyGrant Number
HKU Alzheimer's Disease Research Network
Azalea Endowment Fund
General Research Grant755206M
761609M
Research Grant CouncilN_HKU707/07M
HKU200911159082
University of Hong Kong
Graduate School
Funding Information:

This work is supported by the HKU Alzheimer's Disease Research Network, Azalea (1972) Endowment Fund, General Research Grant (755206M & 761609M), NSFC/RGC Joint Research Scheme (N_HKU707/07M) from Research Grant Council and HKU Seed Funding for Basic Science Research (200911159082) to RCCC. CHLH, SW and QSZ are supported by the Graduate School; YSH is supported by a Postdoctoral Fellowship, The University of Hong Kong.

References

 

Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. The University of Hong Kong
  3. Shenzhen Centre of Disease Control and Prevention
  4. Huazhong University of Science and Technology
  5. Chinese University of Hong Kong
DC FieldValueLanguage
dc.contributor.authorHo, YSen_HK
dc.contributor.authorYang, Xen_HK
dc.contributor.authorLau, JCFen_HK
dc.contributor.authorHung, CHLen_HK
dc.contributor.authorWuwongse, Sen_HK
dc.contributor.authorZhang, Qen_HK
dc.contributor.authorWang, Jen_HK
dc.contributor.authorBaum, Len_HK
dc.contributor.authorSo, KFen_HK
dc.contributor.authorChang, RCCen_HK
dc.date.accessioned2012-05-23T05:42:30Z-
dc.date.available2012-05-23T05:42:30Z-
dc.date.issued2012en_HK
dc.identifier.citationJournal Of Alzheimer's Disease, 2012, v. 28 n. 4, p. 839-854en_HK
dc.identifier.issn1387-2877en_HK
dc.identifier.urihttp://hdl.handle.net/10722/146845-
dc.description.abstractAccumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration. © 2012 - IOS Press and the authors. All rights reserved.en_HK
dc.languageengen_US
dc.publisherI O S Press. The Journal's web site is located at http://www.iospress.nl/html/13872877.phpen_HK
dc.relation.ispartofJournal of Alzheimer's Diseaseen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectAlzheimer's diseaseen_HK
dc.subjectER stressen_HK
dc.subjectokadaic aciden_HK
dc.subjecttau phosphorylationen_HK
dc.subjectthapsigarginen_HK
dc.titleEndoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesisen_HK
dc.typeArticleen_HK
dc.identifier.emailSo, KF:hrmaskf@hkucc.hku.hken_HK
dc.identifier.emailChang, RCC:rccchang@hkucc.hku.hken_HK
dc.identifier.authoritySo, KF=rp00329en_HK
dc.identifier.authorityChang, RCC=rp00470en_HK
dc.description.naturepostprint-
dc.identifier.doi10.3233/JAD-2011-111037en_HK
dc.identifier.pmid22101233-
dc.identifier.scopuseid_2-s2.0-84863242250-
dc.identifier.hkuros199677en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84858059807&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume28en_HK
dc.identifier.issue4en_HK
dc.identifier.spage839en_HK
dc.identifier.epage854en_HK
dc.identifier.isiWOS:000300715600009-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridHo, YS=55078991800en_HK
dc.identifier.scopusauthoridYang, X=55077067100en_HK
dc.identifier.scopusauthoridLau, JCF=55074884700en_HK
dc.identifier.scopusauthoridHung, CHL=55075927700en_HK
dc.identifier.scopusauthoridWuwongse, S=55075071000en_HK
dc.identifier.scopusauthoridZhang, Q=55079403100en_HK
dc.identifier.scopusauthoridWang, J=55079081400en_HK
dc.identifier.scopusauthoridBaum, L=7103310839en_HK
dc.identifier.scopusauthoridSo, KF=34668391300en_HK
dc.identifier.scopusauthoridChang, RCC=7403713410en_HK

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