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Dickkopf-1 overexpression in vitro nominates candidate blood biomarkers relating to Alzheimer's disease pathology

Shi, Liu, Winchester, Laura M., Liu, Benjamine Y., Killick, Richard, Ribe, Elena M., Westwood, Sarah, Baird, Alison L., Buckley, Noel J., Hong, Shengjun, Dobricic, Valerija, Kilpert, Fabian, Franke, Andre, Kiddle, Steven, Sattlecker, Martina, Dobson, Richard, Cuadrado, Antonio, Hye, Abdul, Ashton, Nicholas J., Morgan, Angharad R., Bos, Isabelle, Vos, Stephanie J.B., ten Kate, Mara, Scheltens, Philip, Vandenberghe, Rik, Gabel, Silvy, Meersmans, Karen, Engelborghs, Sebastiaan, De Roeck, Ellen E., Sleegers, Kristel, Frisoni, Giovanni B., Blin, Olivier, Richardson, Jill C., Bordet, Régis, Molinuevo, José L., Rami, Lorena, Wallin, Anders, Kettunen, Petronella, Tsolaki, Magda, Verhey, Frans, Lleó, Alberto, Alcolea, Daniel, Popp, Julius, Peyratout, Gwendoline, Martinez-Lage, Pablo, Tainta, Mikel, Johannsen, Peter, Teunissen, Charlotte E., Freund-Levi, Yvonne, Frölich, Lutz, Legido-Quigley, Cristina, Barkhof, Frederik, Blennow, Kaj, Rasmussen, Katrine Laura, Nordestgaard, Børge Grønne, Frikke-Schmidt, Ruth, Nielsen, Sune Fallgaard, Soininen, Hilkka, Vellas, Bruno, Kloszewska, Iwona, Mecocci, Patrizia, Zetterberg, Henrik, Morgan, B. Paul, Streffer, Johannes, Visser, Pieter Jelle, Bertram, Lars, Nevado-Holgado, Alejo J. and Lovestone, Simon 2020. Dickkopf-1 overexpression in vitro nominates candidate blood biomarkers relating to Alzheimer's disease pathology. Journal of Alzheimer's Disease 77 (3) , pp. 1353-1368. 10.3233/JAD-200208

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Background: 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. Objective: 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. Methods: 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). Results: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 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. Conclusions: 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: IOS Press
ISSN: 1387-2877
Date of First Compliant Deposit: 21 October 2020
Date of Acceptance: 15 July 2020
Last Modified: 29 Jan 2022 11:27

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