Protein disulfide isomerases as CSF biomarkers for the neuronal response to tau pathology

被引：7

作者：

Wolzak, Kimberly ^{[1
,2
,3
]}

Vermunt, Lisa ^{[3
,4
]}

del Campo, Marta ^{[3
,4
,5
,6
]}

Jorge-Oliva, Marta ^{[1
,3
]}

van Ziel, Anna Maria ^{[1
,2
,3
]}

Li, Ka Wan ^{[3
,7
]}

Smit, August B. ^{[3
,7
]}

Chen-Ploktkin, Alice ^{[8
]}

Irwin, David J. ^{[8
,9
]}

Lemstra, Afina W. ^{[3
,10
]}

Pijnenburg, Yolande ^{[3
,10
]}

van der Flier, Wiesje ^{[3
,10
,11
]}

Zetterberg, Henrik ^{[12
,13
,14
,15
,16
]}

Gobom, Johan ^{[12
,13
]}

Blennow, Kaj ^{[12
,13
]}

Visser, Pieter Jelle ^{[3
,10
,17
,18
]}

Teunissen, Charlotte E. ^{[3
,4
]}

Tijms, Betty M. ^{[3
,10
]}

Scheper, Wiep ^{[1
,2
,3
]}

机构：

[1] Vrije Univ Amsterdam, Fac Sci, CNCR, Dept Funct Genom, Amsterdam, Netherlands

[2] Amsterdam Univ Med Ctr UMC, Locat Vrije Univ, Dept Human Genet, Funct Genom Sect, Amsterdam, Netherlands

[3] Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands

[4] Amsterdam Univ Med Ctr UMC, Locat Vrije Univ, Dept Clin Chem, Neurochem Lab, Amsterdam, Netherlands

[5] Univ San Pablo CEU, CEU Univ, Fac Farm, Dept Ciencias Farmaceut & Salud, Madrid, Spain

[6] Pasqual Maragall Fdn, BBRC, Barcelona, Spain

[7] Vrije Univ Amsterdam, Fac Sci, CNCR, Dept Mol & Cellular Neurobiol, Amsterdam, Netherlands

[8] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA USA

[9] Univ Penn, Perelman Sch Med, Penn Frontotemporal Degenerat Ctr, Philadelphia, PA USA

[10] Amsterdam Univ Med Ctr UMC, Locat Vrije Univ, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam, Netherlands

[11] Amsterdam Univ Med Ctr UMC, Locat Vrije Univ, Dept Epidemiol & Data Sci, Amsterdam, Netherlands

[12] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden

[13] Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden

[14] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England

[15] UCL, UK Dementia Res Inst, London, England

[16] Hong Kong Ctr Neurodegenerat Dis, Hong Kong, Peoples R China

[17] Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Maastricht, Netherlands

[18] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden

来源：

ALZHEIMERS & DEMENTIA | 2023年 / 19卷 / 08期

基金：

欧盟地平线“2020”; 欧洲研究理事会;

关键词：

Alzheimer's disease; CSF biomarker; PDI; tau pathology; UPR; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; AGGREGATION; PATHWAY; NEURODEGENERATION; SECRETION; INSIGHTS;

D O I：

10.1002/alz.12978

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

IntroductionCerebrospinal 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-associated unfolded protein response (UPR) activation. MethodsWe 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-AD MBD, n = 310; PRIDE, n = 771). ResultsFirst, we identify members of the protein disulfide isomerase (PDI) family in the neuronal UPR-activated secretome and validate secretion upon tau aggregation in vitro. Next, we demonstrate that PDIA1 and PDIA3 levels correlate with total- and phosphorylated-tau levels in CSF. PDIA1 levels are increased in CSF from AD patients compared to controls and patients with tau-unrelated frontotemporal and Lewy body dementia (LBD). HighlightsNeuronal unfolded protein response (UPR) activation induces the secretion of protein disulfide isomerases (PDIs) in vitro.PDIA1 is secreted upon tau aggregation in neurons in vitro.PDIA1 and PDIA3 levels correlate with total and phosphorylated tau levels in CSF.PDIA1 levels are increased in CSF from Alzheimer's disease (AD) patients compared to controls.PDIA1 levels are not increased in CSF from tau-unrelated frontotemporal dementia (FTD) and Lewy body dementia (LBD) patients.

引用

页码：3563 / 3574

页数：12

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