Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology
Por:
Shi, L, Winchester, LM, Liu, BY, Killick, R, Ribe, EM, Westwood, S, Baird, AL, Buckley, NJ, Hong, SJ, 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
Publicada:
1 ene 2020
Resumen:
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.
Filiaciones:
Shi, L:
Univ Oxford, Dept Psychiat, Oxford, England
Winchester, LM:
Univ Oxford, Dept Psychiat, Oxford, England
Liu, BY:
Univ Oxford, Dept Psychiat, Oxford, England
Killick, R:
Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Inst, Clin Neurosci Inst, London, England
Ribe, EM:
Univ Oxford, Dept Psychiat, Oxford, England
Westwood, S:
Univ Oxford, Dept Psychiat, Oxford, England
Baird, AL:
Univ Oxford, Dept Psychiat, Oxford, England
Buckley, NJ:
Univ Oxford, Dept Psychiat, Oxford, England
Hong, SJ:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Dobricic, V:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Kilpert, F:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Franke, A:
Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Kiddle, S:
Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Inst, Clin Neurosci Inst, London, England
Kings Coll London, MRC Social Genet & Dev Psychiat Ctr, London, England
Sattlecker, M:
Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Inst, Clin Neurosci Inst, London, England
Kings Coll London, MRC Social Genet & Dev Psychiat Ctr, London, England
Dobson, R:
Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Biostat & Hlth Informat, London, England
UCL, Inst Hlth Informat, London, England
Cuadrado, A:
Autonomous Univ Madrid, Fac Med, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Inst Invest Sanitaria La Paz IdiPaz,Inst Invest B, Madrid, Spain
Autonomous Univ Madrid, Fac Med, Dept Biochem, Madrid, Spain
Victor Babes Natl Inst Pathol, Bucharest, Romania
Hye, A:
Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Inst, Clin Neurosci Inst, London, England
Ashton, NJ:
Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Inst, Clin Neurosci Inst, London, England
South London & Maudsley NHS Fdn, NIHR Biomed Res Ctr Mental Hlth, London, England
South London & Maudsley NHS Fdn, Biomed Res Unit Dementia, London, England
Univ Gothenburg, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden
Morgan, AR:
Cardiff Univ, Dementia Res Inst Cardiff, Cardiff, Wales
Bos, I:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr, Med Ctr, Amsterdam, Netherlands
Vos, SJB:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
ten Kate, M:
Vrije Univ Amsterdam, Alzheimer Ctr, Med Ctr, Amsterdam, Netherlands
Scheltens, P:
Vrije Univ Amsterdam, Alzheimer Ctr, Med Ctr, Amsterdam, Netherlands
Vandenberghe, R:
Univ Hosp Leuven, Leuven, Belgium
Gabel, S:
Univ Hosp Leuven, Leuven, Belgium
Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium
Meersmans, K:
Univ Hosp Leuven, Leuven, Belgium
Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium
Engelborghs, S:
Vrije Univ Brussel VUB, Ctr Neurosci, Brussels, Belgium
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
UZ Brussel, Dept Neurol, Brussels, Belgium
De Roeck, EE:
Vrije Univ Brussel VUB, Ctr Neurosci, Brussels, Belgium
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Sleegers, K:
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
VIB, Ctr Mol Neurol, Neurodegenerat Brain Dis Grp, Vib, Belgium
Frisoni, GB:
Univ Geneva, Geneva, Switzerland
IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Brescia, Italy
Blin, O:
AIX Marseille Univ, AP HM, INS, Marseille, France
Richardson, JC:
GlaxoSmithKline R&D, Neurosci Therapeut Area, Stevenage, Herts, England
Bordet, R:
Univ Lille, CHU Lille, INSERM, Lille, France
Molinuevo, JL:
Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Univ Pompeu Fabra, BarcelonaBeta Brain Res Ctr, Barcelona, Spain
Rami, L:
Univ Pompeu Fabra, BarcelonaBeta Brain Res Ctr, Barcelona, Spain
Wallin, A:
Univ Gothenburg, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
Sahlgrens Univ Hosp, Memory Clin, Dept Neuropsychiat, Molndal, Sweden
Kettunen, P:
Univ Gothenburg, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England
Tsolaki, M:
Aristotle Univ Thessaloniki, Ahepa Univ Hosp, Sch Med, Dept Neurol 1, Thessaloniki, Greece
Verhey, F:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Lleo, A:
Hosp Santa Creu & Sant Pau, Dept Neurol, Barcelona, Spain
Alcolea, D:
Hosp Santa Creu & Sant Pau, Dept Neurol, Barcelona, Spain
Popp, J:
Univ Geneva, Geneva, Switzerland
Univ Hosp Lausanne, Dept Psychiat, Lausanne, Switzerland
Geneva Univ Hosp, Dept Psychiat, Geriatr Psychiat, Geneva, Switzerland
Peyratout, G:
Univ Hosp Lausanne, Dept Psychiat, Lausanne, Switzerland
Martinez-Lage, P:
CITA Alzheimer Fdn, San Sebastian, Spain
Tainta, M:
CITA Alzheimer Fdn, San Sebastian, Spain
Org Sanitaria Integrada Goierri Alto Urola, Osakidetza, Spain
Johannsen, P:
Copenhagen Univ Hosp, Rigshosp, Danish Dementia Res Ctr, Copenhagen, Denmark
Teunissen, CE:
Vrije Univ, Amsterdam Univ Med Ctr, Dept Clin Chem, Neurochem Lab,Amsterdam Neurosci, Amsterdam, Netherlands
Freund-Levi, Y:
Orebro Univ, Sch Med Sci, Orebro, Sweden
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden
Kings Coll London, Dept Old Age Psychiat Psychol & Neurosci, London, England
Orebro Univ Sjukhus, Dept Psychiat, Orebro, Sweden
Frolich, L:
Heidelberg Univ, Zent Inst Seel Gesundheit, Dept Geriatr Psychiat, Mannheim, Germany
Legido-Quigley, C:
Kings Coll London, London, England
Steno Diabet Ctr Copenhagen, Syst Med Grp, Gentofte, Denmark
Barkhof, F:
Vrije Univ Amsterdam, Dept Radiol & Nucl Med, Med Ctr, Amsterdam, Netherlands
UCL Inst Neurol & Healthcare Engn, London, England
Blennow, K:
Univ Gothenburg, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Rasmussen, KL:
Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark
Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark
Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark
Nordestgaard, BG:
Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark
Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark
Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark
Copenhagen Univ Hosp, Frederiksberg Hosp, Copenhagen City Heart Study, Frederiksberg, Denmark
Frikke-Schmidt, R:
Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark
Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark
Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark
Nielsen, SF:
Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark
Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark
Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark
Soininen, H:
Univ Eastern Finland, Neurol Inst Clin Med, Kuopio, Finland
Vellas, B:
Univ Paul Sabatier, Toulouse Gerontopole Univ Hosp, INSERM U 558, Toulouse, France
Kloszewska, I:
Med Univ Lodz, Lodz, Poland
Mecocci, P:
Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy
Zetterberg, H:
Univ Gothenburg, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
UCL, England Dementia Res Inst, London, England
UCL Inst Neurol, Dept Neurodegenerat Dis, London, England
Morgan, BP:
Cardiff Univ, Dementia Res Inst Cardiff, Cardiff, Wales
Streffer, J:
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
UCB, Braine Lalleud, Belgium
Janssen R&D LLC, Beerse, Belgium
Visser, PJ:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr, Med Ctr, Amsterdam, Netherlands
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden
Bertram, L:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Univ Oslo, Dept Psychol, Oslo, Norway
Nevado-Holgado, AJ:
Univ Oxford, Dept Psychiat, Oxford, England
Lovestone, S:
Univ Oxford, Dept Psychiat, Oxford, England
Janssen Cilag UK, Wycombe, England
Bronze, Green Published, Green Accepted
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