TY - JOUR

T1 - Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology

AU - Shi, Liu

AU - Winchester, Laura M.

AU - Liu, Benjamine Y.

AU - Killick, Richard

AU - Ribe, Elena M.

AU - Westwood, Sarah

AU - Baird, Alison L.

AU - Buckley, Noel J.

AU - Hong, Shengjun

AU - Dobricic, Valerija

AU - Kilpert, Fabian

AU - Franke, Andre

AU - Kiddle, Steven

AU - Sattlecker, Martina

AU - Dobson, Richard

AU - Cuadrado, Antonio

AU - Hye, Abdul

AU - Ashton, Nicholas J.

AU - Morgan, Angharad R.

AU - Bos, Isabelle

AU - Vos, Stephanie J.B.

AU - Ten Kate, Mara

AU - Scheltens, Philip

AU - Vandenberghe, Rik

AU - Gabel, Silvy

AU - Meersmans, Karen

AU - Engelborghs, Sebastiaan

AU - De Roeck, Ellen E.

AU - Sleegers, Kristel

AU - Frisoni, Giovanni B.

AU - Blin, Olivier

AU - Richardson, Jill C.

AU - Bordet, Régis

AU - Molinuevo, José L.

AU - Rami, Lorena

AU - Wallin, Anders

AU - Kettunen, Petronella

AU - Tsolaki, Magda

AU - Verhey, Frans

AU - Lleó, Alberto

AU - Alcolea, Daniel

AU - Popp, Julius

AU - Peyratout, Gwendoline

AU - Martinez-Lage, Pablo

AU - Tainta, Mikel

AU - Johannsen, Peter

AU - Teunissen, Charlotte E.

AU - Freund-Levi, Yvonne

AU - Frölich, Lutz

AU - Legido-Quigley, Cristina

AU - Barkhof, Frederik

AU - Blennow, Kaj

AU - Rasmussen, Katrine Laura

AU - Nordestgaard, Børge Grønne

AU - Frikke-Schmidt, Ruth

AU - Nielsen, Sune Fallgaard

AU - Soininen, Hilkka

AU - Vellas, Bruno

AU - Kloszewska, Iwona

AU - Mecocci, Patrizia

AU - Zetterberg, Henrik

AU - Morgan, B. Paul

AU - Streffer, Johannes

AU - Visser, Pieter Jelle

AU - Bertram, Lars

AU - Nevado-Holgado, Alejo J.

AU - Lovestone, Simon

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - ATN framework

KW - Dickkopf-1

KW - replication

KW - SomaScan

KW - Wnt signaling

U2 - 10.3233/JAD-200208

DO - 10.3233/JAD-200208

M3 - Journal article

C2 - 32831200

AN - SCOPUS:85092562697

VL - 77

SP - 1353

EP - 1368

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 3

ER -