Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology
Shi, Liu (University of Oxford)
Winchester, Laura M. (University of Oxford)
Liu, Benjamine Y. (University of Oxford)
Killick, Richard (Maurice Wohl Institute Clinical Neuroscience Institute)
Ribe, Elena M. (University of Oxford)
Westwood, Sarah (University of Oxford)
Baird, Alison L. (University of Oxford)
Buckley, Noel J. (University of Oxford)
Hong, Shengjun (University of Lübeck)
Dobricic, Valerija (University of Lübeck)
Kilpert, Fabian (University of Lübeck)
Franke, Andre (Christian-Albrechts-University of Kiel)
Kiddle, Steven (King's College London)
Sattlecker, Martina (King's College London)
Dobson, Richard (University College London)
Cuadrado, Antonio ("Victor Babes" National Institute of Pathology)
Hye, Abdul (Maurice Wohl Institute Clinical Neuroscience Institute)
Ashton, Nicholas J. (University of Gothenburg)
Morgan, Angharad R. (Cardiff University)
Bos, Isabelle (Amsterdam UMC. University Medical Center)
Vos, Stephanie J. B. (Maastricht University)
ten Kate, Mara (Amsterdam UMC. University Medical Center)
Scheltens, Philip (Amsterdam UMC. University Medical Center)
Vandenberghe, Rik (University Hospitals Leuven (Bèlgica))
Gabel, Silvy (Laboratory for Cognitive Neurology)
Meersmans, Karen (Laboratory for Cognitive Neurology)
Engelborghs, Sebastiaan (Universitair Ziekenhuis Brussel-UZ Brussel. Department of Neurology)
De Roeck, Ellen E. (University of Antwerp)
Sleegers, Kristel (Center for Molecular Neurology)
Frisoni, Giovanni B. (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli)
Blin, Olivier (Aix-Marseille Université)
Richardson, Jill C. (GlaxoSmithKline R&D. Neurosciences Therapeutic Area)
Bordet, Régis (University of Lille)
Molinuevo, José Luis (Barcelonaβeta Brain Research Center (BBRC))
Rami Gonzalez, Lorena (Barcelonaβeta Brain Research Center (BBRC))
Wallin, Anders (Sahlgrenska University Hospital (Suècia))
Kettunen, Petronella (University of Oxford)
Tsolaki, Magda (Aristotle University of Thessaloniki)
Verhey, Frans (Maastricht University)
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Alcolea, Daniel (Institut d'Investigació Biomèdica Sant Pau)
Popp, Julius (University of Geneva)
Peyratout, Gwendoline (Lausanne University Hospital)
Martinez-Lage, Pablo (CITA-Alzheimer Foundation (San Sebastian))
Tainta, Mikel (Organización Sanitaria Integrada Goierri)
Johannsen, Peter (Copenhagen University Hospital)
Teunissen, Charlotte E. (Amsterdam UMC. University Medical Center)
Freund-Levi, Yvonne (Department of Psychiatry, Örebro Universitetssjukhus)
Frölich, Lutz (University of Heidelberg)
Legido-Quigley, Cristina (Steno Diabetes Center Copenhagen)
Barkhof, Frederik (UCL Institutes of Neurology and Healthcare Engineering)
Blennow, Kaj (Sahlgrenska University Hospital (Suècia))
Rasmussen, Katrine Laura (University of Copenhagen)
Nordestgaard, Børge Grønne (Copenhagen University Hospital)
Frikke-Schmidt, Ruth (University of Copenhagen)
Nielsen, Sune Fallgaard (Copenhagen University Hospital)
Soininen, Hilkka (University of Eastern Finland)
Vellas, Bruno (Univeriste Paul Sabatier)
Kloszewska, Iwona (Medical University of Lodz)
Mecocci, Patrizia (University of Perugia (Itàlia))
Zetterberg, Henrik (UCL Institute of Neurology (Regne Unit))
Morgan, B. Paul (Cardiff University)
Streffer, Johannes (UCB Pharma (Braine-l'Alleud, Bèlgica))
Visser, Pieter Jelle (Karolinska Institutet (Estocolm, Suècia))
Bertram, Lars (University of Oslo)
Nevado-Holgado, Alejo (University of Oxford)
Lovestone, Simon (University of Oxford)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ 4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0. 72, 0. 81, 0. 88, and 0. 85, respectively. Furthermore, we found that some signature proteins (e. g. , Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	ATN framework ; Dickkopf-1 ; Replication ; SomaScan ; Wnt signaling
Published in:	Journal of Alzheimer's disease, Vol. 77 (september 2020) , p. 1353-1368, ISSN 1875-8908

DOI: 10.3233/JAD-200208
PMID: 32831200

16 p, 903.0 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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