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.
| Original language | English |
|---|---|
| Pages (from-to) | 3563-3574 |
| Number of pages | 12 |
| Journal | Alzheimer's and Dementia |
| Volume | 19 |
| Issue number | 8 |
| Early online date | 24 Feb 2023 |
| DOIs | |
| Publication status | Published - Aug 2023 |
Bibliographical note
Funding Information:W.S. performs contract research for Alzinova and DiscovericBio and received grants from Janssen Pharmaceutica. She is associate editor of Acta Neuropathologica Communications and Alzheimer's Research & Therapy. L.V. received consultancy fees for Roche, paid to her institution. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). C.E.T. has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC‐Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer. She had speaker contracts for Roche, Grifols, Novo Nordisk. All other authors declare no declarations of interest. The in vitro work in this study was supported by Weston Brain Institute #NR160014 and ZonMW Memorabel/Alzheimer Nederland #733050101 to WS. The EMIF‐AD MBD study received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant n°115372) and Zon‐MW Memorabel (733050824). The PRIDE study was supported by Alzheimer Nederland, Selfridges Group Foundation, ZonMW (#73305095007), Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). Collection of patient samples and data from Penn University was supported by National Institute on Aging (P01‐AG066597), National Institute on Aging P30‐AG072979 (formerly P30‐AG10124), National Institute on Aging U19‐AG062418‐03 (formerly NINDSP50‐NS053488‐09)). Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. L.V. received grants from ZonMw, Alzheimer Nederland and OLINK, paid to her institution. M.C. is supported by the attraction talent fellowship of Comunidad de Madrid and San Pablo CEU University. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG‐71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF‐21‐831376‐C, #ADSF‐21‐831381‐C and #ADSF‐21‐831377‐C), the Bluefield Project, the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022‐0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021‐00694), and the UK Dementia Research Institute at UCL (UKDRI‐1003). J.G. is supported by Alzheimerfonden (AF‐930934) and the Foundation of Gamla Tjänarinnor. Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking [JU] under grant agreement No. 101034344grant no) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. C.T. is recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes‐Strijbisfonds. Author disclosures are available in the supporting information .
Publisher Copyright:
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Funding
W.S. performs contract research for Alzinova and DiscovericBio and received grants from Janssen Pharmaceutica. She is associate editor of Acta Neuropathologica Communications and Alzheimer's Research & Therapy. L.V. received consultancy fees for Roche, paid to her institution. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). C.E.T. has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC‐Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer. She had speaker contracts for Roche, Grifols, Novo Nordisk. All other authors declare no declarations of interest. The in vitro work in this study was supported by Weston Brain Institute #NR160014 and ZonMW Memorabel/Alzheimer Nederland #733050101 to WS. The EMIF‐AD MBD study received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant n°115372) and Zon‐MW Memorabel (733050824). The PRIDE study was supported by Alzheimer Nederland, Selfridges Group Foundation, ZonMW (#73305095007), Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). Collection of patient samples and data from Penn University was supported by National Institute on Aging (P01‐AG066597), National Institute on Aging P30‐AG072979 (formerly P30‐AG10124), National Institute on Aging U19‐AG062418‐03 (formerly NINDSP50‐NS053488‐09)). Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. L.V. received grants from ZonMw, Alzheimer Nederland and OLINK, paid to her institution. M.C. is supported by the attraction talent fellowship of Comunidad de Madrid and San Pablo CEU University. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG‐71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF‐21‐831376‐C, #ADSF‐21‐831381‐C and #ADSF‐21‐831377‐C), the Bluefield Project, the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022‐0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021‐00694), and the UK Dementia Research Institute at UCL (UKDRI‐1003). J.G. is supported by Alzheimerfonden (AF‐930934) and the Foundation of Gamla Tjänarinnor. Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking [JU] under grant agreement No. 101034344grant no) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. C.T. is recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes‐Strijbisfonds. Author disclosures are available in the supporting information .
| Funders | Funder number |
|---|---|
| AD Strategic Fund | |
| Comunidad de Madrid and San Pablo CEU University | |
| EPND | |
| EU/EFPIA | 115372 |
| Edwin Bouw Fonds and Gieskes‐Strijbisfonds | |
| Foundation of Gamla Tjänarinnor | |
| National Institute on Aging P30‐AG072979 | |
| National Institute on Aging U19‐AG062418‐03 | |
| Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden | 2022‐0270 |
| Swedish State Support for Clinical Research | 71320 |
| Zon‐MW Memorabel | 733050824 |
| National Institute on Aging | P01‐AG066597 |
| National Institute on Aging | |
| National Multiple Sclerosis Society | |
| Alzheimer's Association | |
| Alzheimer's Drug Discovery Foundation | 201809‐2016862 |
| Alzheimer's Drug Discovery Foundation | |
| Eli Lilly and Company | 160014 |
| Eli Lilly and Company | |
| Familjen Erling-Perssons Stiftelse | |
| Janssen Pharmaceuticals | |
| EU Joint Programme – Neurodegenerative Disease Research | JPND2021‐00694 |
| EU Joint Programme – Neurodegenerative Disease Research | |
| Health~Holland | |
| European Commission | 831434 |
| European Commission | |
| European Research Council | 101053962, 681712 |
| European Research Council | |
| ZonMw | 733050101 |
| ZonMw | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
| Vetenskapsrådet | 2018‐02532 |
| Vetenskapsrådet | |
| Horizon 2020 | 860197 |
| Horizon 2020 | |
| Innovative Medicines Initiative | |
| Alzheimer Nederland | |
| UK Dementia Research Institute | UKDRI‐1003, AF‐930934 |
| UK Dementia Research Institute | |
| Olav Thon Stiftelsen | |
| Selfridges Group Foundation | 73305095007, 20106 |
| Selfridges Group Foundation |
Keywords
- Alzheimer's disease
- CSF biomarker
- PDI
- tau pathology
- UPR