{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T09:13:22Z","timestamp":1791105202458,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,2,17]],"date-time":"2012-02-17T00:00:00Z","timestamp":1329436800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100008398","name":"Internationale Stichting Alzheimer Onderzoek","doi-asserted-by":"crossref","award":["ISAO #07506"],"award-info":[{"award-number":["ISAO #07506"]}],"id":[{"id":"10.13039\/501100008398","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Netherlands Organisation for Scientific Research"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2012,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2010tau) in Alzheimer's disease (AD). As well as increased presence of intracellular p\u2010tau, AD brains are characterized by extracellular deposits of \u03b2 amyloid (A\u03b2). Recent <jats:italic>in vitro<\/jats:italic> studies have shown that A\u03b2 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\u201017) which carry mutations in the gene encoding for tau (<jats:italic>MAPT<\/jats:italic>). The presence of phosphorylated pancreatic ER kinase (pPERK) and phosphorylated inositol requiring enzyme 1\u03b1 (pIRE1), which are indicative of an activated UPR, was assessed by immunohistochemistry in cases neuropathologically defined as frontotemporal lobar degeneration with tau pathology (FTLD\u2010tau). Increased presence of UPR activation markers pPERK and pIRE1 was observed in neurons and glia in FTLD\u2010tau cases, in contrast to FTLD subtypes negative for tau pathology or in non\u2010neurological controls. pPERK and pIRE1 were also prominently present in relatively young carriers of <jats:italic>MAPT<\/jats:italic> mutation. A strong association between the presence of UPR activation markers and p\u2010tau was observed in the hippocampus of FTLD\u2010tau cases. Double immunohistochemical staining on FTLD\u2010tau cases revealed that UPR activation is predominantly observed in neurons that show diffuse staining of p\u2010tau. These data demonstrate that UPR activation is intimately connected with the accumulation and aggregation of p\u2010tau, and occurs independently from A\u03b2 deposits. Our findings provide new pathological insight into the close association between p\u2010tau and UPR activation in tauopathies. Copyright \u00a9 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.3969","type":"journal-article","created":{"date-parts":[[2011,11,21]],"date-time":"2011-11-21T04:40:31Z","timestamp":1321850431000},"page":"693-702","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":178,"title":["The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies"],"prefix":"10.1002","volume":"226","author":[{"given":"Diana AT","family":"Nijholt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise S","family":"van Haastert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke 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