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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 ?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.

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.

SUBMITTER: Shi L

PROVIDER: S-EPMC7683080 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

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

Journal of Alzheimer's disease : JAD 20200101 3

<h4>Background</h4>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.<h4>Objective</h4>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 we ...[more]

PMID: 32831200

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Project description:Background and Objective: Plasma biomarkers for the diagnosis and stratification of Alzheimer's disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers. Methods: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals. Results: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc. Conclusions: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.

Project description:Ninety percent of patients with esophageal adenocarcinoma ultimately die of their disease, highlighting the need for novel therapeutic targets. The goal of this study was to define the functional significance of overexpression of Dickkopf-3 (DKK3) in esophageal adenocarcinoma.DKK3 expression was analyzed by real-time polymerase chain reaction in 95 chemonaive and 21 chemoresistant esophageal adenocarcinomas. The esophageal adenocarcinoma cell line OE33 was stably transfected with DKK3 (OE33/DKK3) and evaluated using WST-1 (Roche, Basel, Switzerland), Matrigel (BD Biosciences, San Jose, Calif), endothelial tube formation, and chemosensitivity assays. Tumorigenesis was evaluated by injecting 1 × 10(6) OE33/DKK3 and vector cells in NOD/SCID? mice.DKK3 was overexpressed (>2-fold) in 75.8% (72/95) of esophageal adenocarcinomas. DKK3 protein was present at moderate to high levels in 46.8% (29/62) of esophageal adenocarcinomas on tissue microarray. Stable transfection of DKK3 significantly increased proliferation (P < .05) and Matrigel invasion (P < .001). Levels of SMAD4, a key mediator of the transforming growth factor-ß pathway, increased after activin treatment of OE33/DKK3, and siSMAD4 significantly decreased Matrigel invasion, suggesting that DKK3 acts through the transforming growth factor-? pathway. OE33/DKK3 cells increased endothelial tube formation and were significantly more resistant to 5-fluorouracil and cisplatin, and DKK3 expression was significantly higher in chemoresistant esophageal adenocarcinomas (P < .005). In NOD/SCID? mice, OE33/DKK3 cells resulted in tumors at all sites (8/8), whereas vector cells grew in only 1 of 8 sites. Nodal metastases were also significantly increased in patients with esophageal adenocarcinomas highly overexpressing DKK3, 28 of 32 (88%) versus 42 of 63 (68%) (P < .05).These findings suggest that DKK3 may be important in mediating invasion in esophageal adenocarcinoma and could be a novel target in the treatment and prevention of metastatic disease.

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

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

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