File Download
 
Links for fulltext
(May Require Subscription)
 
Supplementary

Article: Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis
  • Basic View
  • Metadata View
  • XML View
TitleEndoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis
 
AuthorsHo, YS2
Yang, X2 3
Lau, JCF2
Hung, CHL2
Wuwongse, S2 1
Zhang, Q2
Wang, J4
Baum, L5
So, KF2
Chang, RCC2
 
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
2012 Impact Factor: 4.174
2012 SCImago Journal Rankings: 1.373
 
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
 
DC FieldValue
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.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
2012 Impact Factor: 4.174
2012 SCImago Journal Rankings: 1.373
 
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
 
<?xml encoding="utf-8" version="1.0"?>
<item><contributor.author>Ho, YS</contributor.author>
<contributor.author>Yang, X</contributor.author>
<contributor.author>Lau, JCF</contributor.author>
<contributor.author>Hung, CHL</contributor.author>
<contributor.author>Wuwongse, S</contributor.author>
<contributor.author>Zhang, Q</contributor.author>
<contributor.author>Wang, J</contributor.author>
<contributor.author>Baum, L</contributor.author>
<contributor.author>So, KF</contributor.author>
<contributor.author>Chang, RCC</contributor.author>
<date.accessioned>2012-05-23T05:42:30Z</date.accessioned>
<date.available>2012-05-23T05:42:30Z</date.available>
<date.issued>2012</date.issued>
<identifier.citation>Journal Of Alzheimer&apos;s Disease, 2012, v. 28 n. 4, p. 839-854</identifier.citation>
<identifier.issn>1387-2877</identifier.issn>
<identifier.uri>http://hdl.handle.net/10722/146845</identifier.uri>
<description.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&apos;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-eIF2&#945;) 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-eIF2&#945;, 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. &#169; 2012 - IOS Press and the authors. All rights reserved.</description.abstract>
<language>eng</language>
<publisher>I O S Press. The Journal&apos;s web site is located at http://www.iospress.nl/html/13872877.php</publisher>
<relation.ispartof>Journal of Alzheimer&apos;s Disease</relation.ispartof>
<rights>Creative Commons: Attribution 3.0 Hong Kong License</rights>
<subject>Alzheimer&apos;s disease</subject>
<subject>ER stress</subject>
<subject>okadaic acid</subject>
<subject>tau phosphorylation</subject>
<subject>thapsigargin</subject>
<title>Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer&apos;s disease pathogenesis</title>
<type>Article</type>
<description.nature>postprint</description.nature>
<identifier.doi>10.3233/JAD-2011-111037</identifier.doi>
<identifier.pmid>22101233</identifier.pmid>
<identifier.scopus>eid_2-s2.0-84863242250</identifier.scopus>
<identifier.hkuros>199677</identifier.hkuros>
<relation.references>http://www.scopus.com/mlt/select.url?eid=2-s2.0-84858059807&amp;selection=ref&amp;src=s&amp;origin=recordpage</relation.references>
<identifier.volume>28</identifier.volume>
<identifier.issue>4</identifier.issue>
<identifier.spage>839</identifier.spage>
<identifier.epage>854</identifier.epage>
<identifier.isi>WOS:000300715600009</identifier.isi>
<publisher.place>Netherlands</publisher.place>
<bitstream.url>http://hub.hku.hk/bitstream/10722/146845/1/Content.pdf</bitstream.url>
</item>
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