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

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; Regis Bordet; Jose L. Molinuevo; Lorena Rami; Anders Wallin; Petronella Kettunen; Magda Tsolaki; Frans Verhey; Alberto Lleo; Daniel Alcolea; Julius Popp; Gwendoline Peyratout; Pablo Martinez-Lage; Mikel Tainta; Peter Johannsen; Charlotte E. Teunissen; Yvonne Freund-Levi; Lutz Frolich; Cristina Legido-Quigley; Frederik Barkhof; Kaj Blennow; Katrine Laura Rasmussen; Borge Gronne 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

doi:10.3233/JAD-200208

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

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 BosStephanie 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, Regis Bordet, Jose L. Molinuevo, Lorena Rami, Anders Wallin, Petronella Kettunen, Magda Tsolaki, Frans Verhey, Alberto Lleo, Daniel Alcolea, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Peter Johannsen, Charlotte E. Teunissen, Yvonne Freund-Levi, Lutz Frolich, Cristina Legido-Quigley, Frederik Barkhof, Kaj Blennow, Katrine Laura Rasmussen, Borge Gronne 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

4 Citations (Web of Science)

Abstract

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 epsilon 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.

Conclusion: 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 the ATN framework as well as predict disease severity and progression in vivo.

Original language	English
Pages (from-to)	1353-1368
Number of pages	16
Journal	Journal of Alzheimer's Disease
Volume	77
Issue number	3
DOIs	https://doi.org/10.3233/JAD-200208
Publication status	Published - 2020

Keywords

ATN framework
Dickkopf-1
replication
SomaScan
Wnt signaling
BETA-AMYLOID TOXICITY
MENDELIAN RANDOMIZATION
NEURODEGENERATION
DEGENERATION
PATHOGENESIS
METAANALYSIS
ACTIVATION
INDUCTION
PATHWAY
MODELS

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Cite this

Shi, L., Winchester, L. M., Liu, B. Y., Killick, R., Ribe, E. M., Westwood, S., Baird, A. L., Buckley, N. J., Hong, S., Dobricic, V., Kilpert, F., Franke, A., Kiddle, S., Sattlecker, M., Dobson, R., Cuadrado, A., Hye, A., Ashton, N. J., Morgan, A. R., ... Lovestone, S. (2020). Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology. Journal of Alzheimer's Disease, 77(3), 1353-1368. https://doi.org/10.3233/JAD-200208

@article{58e1f81ed02f41bf97581eb28b2f91c5,

title = "Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology",

abstract = "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 epsilon 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.Conclusion: 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 the ATN framework as well as predict disease severity and progression in vivo.",

keywords = "ATN framework, Dickkopf-1, replication, SomaScan, Wnt signaling, BETA-AMYLOID TOXICITY, MENDELIAN RANDOMIZATION, NEURODEGENERATION, DEGENERATION, PATHOGENESIS, METAANALYSIS, ACTIVATION, INDUCTION, PATHWAY, MODELS",

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

note = "Funding Information: This research was conducted as part of the EMIF-AD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n◦ 115372, resources of which are composed of financial contribution from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies{\textquoteright} in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onder-zoek (grant numbers #11020, #13007 and #15005). The Lausanne cohort study was supported by a grant from the Swiss National Research Foundation to JP (SNF 320030 141179). RV is a senior clinical investigator of the Flemish Research Foundation (FWO). JS is currently an employee of UCB, Braine-l{\textquoteright}Alleud, Belgium. The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). We acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIB-CMN is funded in part by the University of Antwerp Research Fund. FB is supported by the Publisher Copyright: {\textcopyright} 2020 - IOS Press and the authors. All rights reserved.",

year = "2020",

doi = "10.3233/JAD-200208",

language = "English",

volume = "77",

pages = "1353--1368",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "IOS Press",

number = "3",

}

Shi, L, Winchester, LM, Liu, BY, Killick, R, Ribe, EM, Westwood, S, Baird, AL, Buckley, NJ, Hong, S, Dobricic, V, Kilpert, F, Franke, A, Kiddle, S, Sattlecker, M, Dobson, R, Cuadrado, A, Hye, A, Ashton, NJ, Morgan, AR, Bos, I, Vos, SJB, ten Kate, M, Scheltens, P, Vandenberghe, R, Gabel, S, Meersmans, K, Engelborghs, S, De Roeck, EE, Sleegers, K, Frisoni, GB, Blin, O, Richardson, JC, Bordet, R, Molinuevo, JL, Rami, L, Wallin, A, Kettunen, P, Tsolaki, M, Verhey, F, Lleo, A, Alcolea, D, Popp, J, Peyratout, G, Martinez-Lage, P, Tainta, M, Johannsen, P, Teunissen, CE, Freund-Levi, Y, Frolich, L, Legido-Quigley, C, Barkhof, F, Blennow, K, Rasmussen, KL, Nordestgaard, BG, Frikke-Schmidt, R, Nielsen, SF, Soininen, H, Vellas, B, Kloszewska, I, Mecocci, P, Zetterberg, H, Morgan, BP, Streffer, J, Visser, PJ, Bertram, L, Nevado-Holgado, AJ & Lovestone, S 2020, 'Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology', Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1353-1368. https://doi.org/10.3233/JAD-200208

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, Regis

AU - Molinuevo, Jose L.

AU - Rami, Lorena

AU - Wallin, Anders

AU - Kettunen, Petronella

AU - Tsolaki, Magda

AU - Verhey, Frans

AU - Lleo, 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 - Frolich, Lutz

AU - Legido-Quigley, Cristina

AU - Barkhof, Frederik

AU - Blennow, Kaj

AU - Rasmussen, Katrine Laura

AU - Nordestgaard, Borge Gronne

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

N1 - Funding Information: This research was conducted as part of the EMIF-AD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n◦ 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onder-zoek (grant numbers #11020, #13007 and #15005). The Lausanne cohort study was supported by a grant from the Swiss National Research Foundation to JP (SNF 320030 141179). RV is a senior clinical investigator of the Flemish Research Foundation (FWO). JS is currently an employee of UCB, Braine-l’Alleud, Belgium. The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). We acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIB-CMN is funded in part by the University of Antwerp Research Fund. FB is supported by the Publisher Copyright: © 2020 - IOS Press and the authors. All rights reserved.

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 epsilon 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.Conclusion: 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 the ATN framework 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 epsilon 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.Conclusion: 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 the ATN framework as well as predict disease severity and progression in vivo.

KW - ATN framework

KW - Dickkopf-1

KW - replication

KW - SomaScan

KW - Wnt signaling

KW - BETA-AMYLOID TOXICITY

KW - MENDELIAN RANDOMIZATION

KW - NEURODEGENERATION

KW - DEGENERATION

KW - PATHOGENESIS

KW - METAANALYSIS

KW - ACTIVATION

KW - INDUCTION

KW - PATHWAY

KW - MODELS

U2 - 10.3233/JAD-200208

DO - 10.3233/JAD-200208

M3 - Article

C2 - 32831200

SN - 1387-2877

VL - 77

SP - 1353

EP - 1368

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

IS - 3

ER -