Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
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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, Lovestone Simon
Аннотация
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.