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

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  • Liu Shi
  • Laura M Winchester
  • Benjamine Y Liu
  • Richard Killick
  • Elena M Ribe
  • Sarah Westwood
  • Alison L Baird
  • Noel J Buckley
  • Shengjun Hong
  • Valerija Dobricic
  • Fabian Kilpert
  • Andre Franke
  • Steven Kiddle
  • Martina Sattlecker
  • Richard Dobson
  • Antonio Cuadrado
  • Abdul Hye
  • Nicholas J Ashton
  • Angharad R Morgan
  • Isabelle Bos
  • Stephanie J B Vos
  • Mara Ten Kate
  • Philip Scheltens
  • Rik Vandenberghe
  • Silvy Gabel
  • Karen Meersmans
  • Sebastiaan Engelborghs
  • Ellen E De Roeck
  • Kristel Sleegers
  • Giovanni B Frisoni
  • Olivier Blin
  • Jill C Richardson
  • Régis Bordet
  • José L Molinuevo
  • Lorena Rami
  • Anders Wallin
  • Petronella Kettunen
  • Magda Tsolaki
  • Frans Verhey
  • Alberto Lleó
  • Daniel Alcolea
  • Julius Popp
  • Gwendoline Peyratout
  • Pablo Martinez-Lage
  • Mikel Tainta
  • Peter Johannsen
  • Charlotte E Teunissen
  • Yvonne Freund-Levi
  • Lutz Frölich
  • Cristina Legido-Quigley
  • Frederik Barkhof
  • Kaj Blennow
  • Katrine Laura Rasmussen
  • Børge Grønne Nordestgaard
  • Ruth Frikke-Schmidt
  • Sune Fallgaard Nielsen
  • Hilkka Soininen
  • Bruno Vellas
  • Iwona Kloszewska
  • Patrizia Mecocci
  • Henrik Zetterberg
  • B Paul Morgan
  • Johannes Streffer
  • Pieter Jelle Visser
  • Lars Bertram
  • Alejo J Nevado-Holgado
  • Simon Lovestone
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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 ϵ4 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.

Original languageEnglish
JournalJournal of Alzheimer's Disease
Volume77
Issue number3
Pages (from-to)1353-1368
Number of pages16
ISSN1387-2877
DOIs
Publication statusPublished - 2020

    Research areas

  • ATN framework, Dickkopf-1, replication, SomaScan, Wnt signaling

ID: 61261692