PMID- 22102449
OWN - NLM
STAT- MEDLINE
DCOM- 20120427
LR  - 20211203
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 226
IP  - 5
DP  - 2012 Apr
TI  - The unfolded protein response is associated with early tau pathology in the 
      hippocampus of tauopathies.
PG  - 693-702
LID - 10.1002/path.3969 [doi]
AB  - The unfolded protein response (UPR) is a stress response activated upon disturbed 
      homeostasis in the endoplasmic reticulum (ER). Previously, we reported that the 
      activation of the UPR closely correlates with the presence of phosphorylated tau 
      (p-tau) in Alzheimer's disease (AD). As well as increased presence of 
      intracellular p-tau, AD brains are characterized by extracellular deposits of beta 
      amyloid (Abeta). Recent in vitro studies have shown that Abeta can induce ER stress and 
      activation of the UPR. The aim of the present study is to investigate UPR 
      activation in sporadic tauopathies like progressive supranuclear palsy (PSP) and 
      Pick's disease (PiD), and familial cases with frontotemporal dementia and 
      parkinsonism linked to chromosome 17 (FTDP-17) which carry mutations in the gene 
      encoding for tau (MAPT). The presence of phosphorylated pancreatic ER kinase 
      (pPERK) and phosphorylated inositol requiring enzyme 1alpha (pIRE1), which are 
      indicative of an activated UPR, was assessed by immunohistochemistry in cases 
      neuropathologically defined as frontotemporal lobar degeneration with tau 
      pathology (FTLD-tau). Increased presence of UPR activation markers pPERK and 
      pIRE1 was observed in neurons and glia in FTLD-tau cases, in contrast to FTLD 
      subtypes negative for tau pathology or in non-neurological controls. pPERK and 
      pIRE1 were also prominently present in relatively young carriers of MAPT 
      mutation. A strong association between the presence of UPR activation markers and 
      p-tau was observed in the hippocampus of FTLD-tau cases. Double 
      immunohistochemical staining on FTLD-tau cases revealed that UPR activation is 
      predominantly observed in neurons that show diffuse staining of p-tau. These data 
      demonstrate that UPR activation is intimately connected with the accumulation and 
      aggregation of p-tau, and occurs independently from Abeta deposits. Our findings 
      provide new pathological insight into the close association between p-tau and UPR 
      activation in tauopathies.
CI  - Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by 
      John Wiley & Sons, Ltd.
FAU - Nijholt, Diana A T
AU  - Nijholt DA
AD  - Department of Genome Analysis, Academic Medical Center, University of Amsterdam, 
      Amsterdam, The Netherlands.
FAU - van Haastert, Elise S
AU  - van Haastert ES
FAU - Rozemuller, Annemieke J M
AU  - Rozemuller AJ
FAU - Scheper, Wiep
AU  - Scheper W
FAU - Hoozemans, Jeroen J M
AU  - Hoozemans JJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120217
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Biomarkers)
RN  - 0 (MAPT protein, human)
RN  - 0 (tau Proteins)
RN  - EC 2.7.11.1 (ERN1 protein, human)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 3.1.- (Endoribonucleases)
SB  - IM
CIN - J Pathol. 2012 Apr;226(5):687-92. PMID: 22190226
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Autopsy
MH  - Biomarkers/analysis
MH  - Case-Control Studies
MH  - Endoribonucleases/analysis
MH  - Female
MH  - Hippocampus/*chemistry/pathology
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/analysis
MH  - Tauopathies/genetics/*metabolism
MH  - *Unfolded Protein Response
MH  - Up-Regulation
MH  - eIF-2 Kinase/analysis
MH  - tau Proteins/*analysis/genetics
EDAT- 2011/11/22 06:00
MHDA- 2012/04/28 06:00
CRDT- 2011/11/22 06:00
PHST- 2011/07/08 00:00 [received]
PHST- 2011/10/21 00:00 [revised]
PHST- 2011/11/09 00:00 [accepted]
PHST- 2011/11/22 06:00 [entrez]
PHST- 2011/11/22 06:00 [pubmed]
PHST- 2012/04/28 06:00 [medline]
AID - 10.1002/path.3969 [doi]
PST - ppublish
SO  - J Pathol. 2012 Apr;226(5):693-702. doi: 10.1002/path.3969. Epub 2012 Feb 17.