{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:00:26Z","timestamp":1791547226537,"version":"4.3.4"},"reference-count":55,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T00:00:00Z","timestamp":1677196800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>Cerebrospinal fluid (CSF) biomarkers for specific cellular disease processes are lacking for tauopathies. In this translational study we aimed to identify CSF biomarkers reflecting early tau pathology\u2010associated unfolded protein response (UPR) activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We employed mass spectrometry proteomics and targeted immunoanalysis in a combination of biomarker discovery in primary mouse neurons in vitro and validation in patient CSF from two independent large multicentre cohorts (EMIF\u2010AD MBD, <jats:italic>n<\/jats:italic>\u00a0=\u00a0310; PRIDE, <jats:italic>n<\/jats:italic>\u00a0=\u00a0771).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>First, we identify members of the protein disulfide isomerase (PDI) family in the neuronal UPR\u2010activated secretome and validate secretion upon tau aggregation in vitro. Next, we demonstrate that PDIA1 and PDIA3 levels correlate with total\u2010 and phosphorylated\u2010tau levels in CSF. PDIA1 levels are increased in CSF from AD patients compared to controls and patients with tau\u2010unrelated frontotemporal and Lewy body dementia (LBD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Neuronal unfolded protein response (UPR) activation induces the secretion of protein disulfide isomerases (PDIs) in vitro.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PDIA1 is secreted upon tau aggregation in neurons in vitro.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PDIA1 and PDIA3 levels correlate with total and phosphorylated tau levels in CSF.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PDIA1 levels are increased in CSF from Alzheimer's disease (AD) patients compared to controls.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PDIA1 levels are not increased in CSF from tau\u2010unrelated frontotemporal dementia (FTD) and Lewy body dementia (LBD) patients.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.12978","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T05:35:19Z","timestamp":1677216919000},"page":"3563-3574","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Protein disulfide isomerases as CSF biomarkers for the neuronal response to tau pathology"],"prefix":"10.1002","volume":"19","author":[{"given":"Kimberly","family":"Wolzak","sequence":"first","affiliation":[{"name":"Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Faculty of Science Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Functional Genomics Section, Department of Human Genetics Amsterdam University Medical Centers (UMC) location Vrije Universiteit  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience, Neurodegeneration  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Vermunt","sequence":"additional","affiliation":[{"name":"Amsterdam Neuroscience, Neurodegeneration  Amsterdam the Netherlands"},{"name":"Neurochemistry Laboratory, Department of Clinical Chemistry Amsterdam University Medical Centers (UMC) location Vrije Universiteit  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta del","family":"Campo","sequence":"additional","affiliation":[{"name":"Amsterdam Neuroscience, Neurodegeneration  Amsterdam the Netherlands"},{"name":"Neurochemistry Laboratory, Department of Clinical Chemistry Amsterdam University Medical Centers (UMC) location Vrije Universiteit  Amsterdam the Netherlands"},{"name":"Departamento de Ciencias Farmac\u00e9uticas y de la Salud, Facultad de Farmacia Universidad San Pablo\u2010 CEU, CEU Universities  Madrid Spain"},{"name":"Barcelona\u03b2eta Brain Research Center (BBRC) Pasqual Maragall 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka Wan","family":"Li","sequence":"additional","affiliation":[{"name":"Amsterdam Neuroscience, Neurodegeneration  Amsterdam the Netherlands"},{"name":"Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research (CNCR) Faculty of Science, Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"August B.","family":"Smit","sequence":"additional","affiliation":[{"name":"Amsterdam Neuroscience, Neurodegeneration  Amsterdam the Netherlands"},{"name":"Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research (CNCR) Faculty of Science, Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Chen\u2010Ploktkin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman 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