Protein disulfide isomerases as CSF biomarkers for the neuronal response to tau pathology
Alzheimer's & Dementia, 2023
Wolzak K., Vermunt L., Campo M., Jorge‐Oliva M., van Ziel A., Li K., Smit A., Chen‐Ploktkin A., Irwin D., Lemstra A., Pijnenburg Y., van der Flier W., Zetterberg H., Gobom J., Blennow K., Visser P., Teunissen C., Tijms B., Scheper W.
Disease area | Application area | Sample type | Products |
---|---|---|---|
Neurology | Pathophysiology | CSF | Olink Target 96 |
Abstract
INTRODUCTION
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‐associated unfolded protein response (UPR) activation.
METHODS
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‐AD MBD, n = 310; PRIDE, n = 771).
RESULTS
First, 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).
Highlights
Neuronal 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.