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

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TitleEndoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis
AuthorsHo, YS3
Yang, X2 3
Lau, JCF3
Hung, CHL3
Wuwongse, S1 3
Zhang, Q3
Wang, J4
Baum, L5
So, KF3
Chang, RCC3
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
CitationJournal Of Alzheimer's Disease, 2012, v. 28 n. 4, p. 839-854 [How to Cite?]
DOI: http://dx.doi.org/10.3233/JAD-2011-111037
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.
ISSN1387-2877
2011 Impact Factor: 3.745
2011 SCImago Journal Rankings: 0.268
DOIhttp://dx.doi.org/10.3233/JAD-2011-111037
ISI Accession Number IDWOS:000300715600009
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.

ReferencesReferences in Scopus
GrantsElucidating the biological mechanisms of transforming autophagy into apoptosis in hippocampal neurons exposed to low molecular weight beta-amyloid peptide
DC Field
Value
dc.contributor.authorHo, YS
dc.contributor.authorYang, X
dc.contributor.authorLau, JCF
dc.contributor.authorHung, CHL
dc.contributor.authorWuwongse, S
dc.contributor.authorZhang, Q
dc.contributor.authorWang, J
dc.contributor.authorBaum, L
dc.contributor.authorSo, KF
dc.contributor.authorChang, RCC
dc.date.accessioned2012-05-23T05:42:30Z
dc.date.available2012-05-23T05:42:30Z
dc.date.issued2012
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.
dc.description.grantElucidating the biological mechanisms of transforming autophagy into apoptosis in hippocampal neurons exposed to low molecular weight beta-amyloid peptide
dc.description.grantcode101768
dc.description.naturepostprint
dc.identifier.citationJournal Of Alzheimer's Disease, 2012, v. 28 n. 4, p. 839-854 [How to Cite?]
DOI: http://dx.doi.org/10.3233/JAD-2011-111037
dc.identifier.doihttp://dx.doi.org/10.3233/JAD-2011-111037
dc.identifier.epage854
dc.identifier.hkuros199677
dc.identifier.isiWOS:000300715600009
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.

dc.identifier.issn1387-2877
2011 Impact Factor: 3.745
2011 SCImago Journal Rankings: 0.268
dc.identifier.issue4
dc.identifier.pmid22101233
dc.identifier.scopuseid_2-s2.0-84863242250
dc.identifier.spage839
dc.identifier.urihttp://hdl.handle.net/10722/146845
dc.identifier.volume28
dc.languageeng
dc.publisherI O S Press. The Journal's web site is located at http://www.iospress.nl/html/13872877.php
dc.publisher.placeNetherlands
dc.relation.ispartofJournal of Alzheimer's Disease
dc.relation.referencesReferences in Scopus
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
dc.subjectAlzheimer's disease
dc.subjectER stress
dc.subjectokadaic acid
dc.subjecttau phosphorylation
dc.subjectthapsigargin
dc.titleEndoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Shenzhen Centre of Disease Control and Prevention
  3. The University of Hong Kong
  4. Huazhong University of Science and Technology
  5. Chinese University of Hong Kong