Felix Kork1, Joachim Jankowski1, Anand Goswami1, Joachim Weis1, Gary Brook1, Alfred Yamoah1, Jasper Anink1, Eleonora Aronica1, Stefan Fritz1, Carmen Huck1, Carola Schipke1, Oliver Peters1, Martin Tepel1, Heidi Noels1, Vera Jankowski2. 1. From the Institute for Molecular Cardiovascular Research (F.K., J.J., H.N., V.J.), Department of Anesthesiology (F.K.), and Institute of Neuropathology (A.G., J.W., G.B., A.Y.), Medical Faculty, RWTH Aachen University, Germany; School for Cardiovascular Diseases (J.J.), Maastricht University; Department of (Neuro) Pathology (J.A., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; mfd Diagnostics GmbH (S.F., C.H.), Wendelsheim; Charité-Universitätsmedizin Berlin (C.S., O.P.), corporate member of Freie Universität Berlin; Humboldt-Universität zu Berlin (C.S., O.P.); Berlin Institute of Health (C.S., O.P.), German Center for Neurodegenerative; Experimental and Clinical Research Center (C.S., O.P.), Memory Clinic, Berlin, Germany; and Department of Nephrology (M.T.), Odense University Hospital, Denmark. 2. From the Institute for Molecular Cardiovascular Research (F.K., J.J., H.N., V.J.), Department of Anesthesiology (F.K.), and Institute of Neuropathology (A.G., J.W., G.B., A.Y.), Medical Faculty, RWTH Aachen University, Germany; School for Cardiovascular Diseases (J.J.), Maastricht University; Department of (Neuro) Pathology (J.A., E.A.), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; mfd Diagnostics GmbH (S.F., C.H.), Wendelsheim; Charité-Universitätsmedizin Berlin (C.S., O.P.), corporate member of Freie Universität Berlin; Humboldt-Universität zu Berlin (C.S., O.P.); Berlin Institute of Health (C.S., O.P.), German Center for Neurodegenerative; Experimental and Clinical Research Center (C.S., O.P.), Memory Clinic, Berlin, Germany; and Department of Nephrology (M.T.), Odense University Hospital, Denmark. vjankowski@ukaachen.de.
Abstract
OBJECTIVE: To isolate and identify a new, as yet unknown molecule in CSF that could serve as marker for Alzheimer disease. METHODS: We immunized mice with human CSF and fused hybridomas for monoclonal antibodies and screened these antibodies for their capacity to discriminate CSF of patients with Alzheimer disease from CSF of controls. We then chromatographically isolated the antigen to the best discriminating antibody and identified the antigen using mass spectrometric methods. Thereafter, we quantified the CSF concentration of the antigen in a new cohort of patients with Alzheimer disease and controls and performed immunohistochemistry of postmortem brain tissue derived from patients with Alzheimer disease and controls. RESULTS: We generated >200 hybridomas and selected 1 antibody that discriminated CSF from patients with Alzheimer disease from that of controls. We identified golgin A4 as the antigen detected by this antibody. Golgin A4 concentration was significantly higher in CSF from patients with Alzheimer disease than in CSF of controls (145 [interquartile range 125-155] vs 115 [ 99-128] pg/mL, p < 0.001) and demonstrated a substantial discriminative power (area under the receiver operating characteristic curve 0.80, 95% confidence interval 0.67-0.94). Immunohistochemistry of postmortem brain sections from patients with Alzheimer disease revealed a significant accumulation of golgin A4 in granulovacuolar degeneration bodies (GVBs). CONCLUSIONS: These results support the notion that golgin A4 could serve as a diagnostic marker in Alzheimer disease. For validation of this notion, prospective multicenter diagnostic studies will evaluate golgin A4 as diagnostic marker for Alzheimer disease. Furthermore, it has to be determined whether the association of golgin A4 with GVBs is an epiphenomenon or whether golgin A4 plays a more direct role in Alzheimer disease, allowing it to serve as a target in therapeutic treatment strategies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that elevated CSF golgin A4 levels identify patients with Alzheimer disease.
OBJECTIVE: To isolate and identify a new, as yet unknown molecule in CSF that could serve as marker for Alzheimer disease. METHODS: We immunized mice with humanCSF and fused hybridomas for monoclonal antibodies and screened these antibodies for their capacity to discriminate CSF of patients with Alzheimer disease from CSF of controls. We then chromatographically isolated the antigen to the best discriminating antibody and identified the antigen using mass spectrometric methods. Thereafter, we quantified the CSF concentration of the antigen in a new cohort of patients with Alzheimer disease and controls and performed immunohistochemistry of postmortem brain tissue derived from patients with Alzheimer disease and controls. RESULTS: We generated >200 hybridomas and selected 1 antibody that discriminated CSF from patients with Alzheimer disease from that of controls. We identified golgin A4 as the antigen detected by this antibody. Golgin A4 concentration was significantly higher in CSF from patients with Alzheimer disease than in CSF of controls (145 [interquartile range 125-155] vs 115 [ 99-128] pg/mL, p < 0.001) and demonstrated a substantial discriminative power (area under the receiver operating characteristic curve 0.80, 95% confidence interval 0.67-0.94). Immunohistochemistry of postmortem brain sections from patients with Alzheimer disease revealed a significant accumulation of golgin A4 in granulovacuolar degeneration bodies (GVBs). CONCLUSIONS: These results support the notion that golgin A4 could serve as a diagnostic marker in Alzheimer disease. For validation of this notion, prospective multicenter diagnostic studies will evaluate golgin A4 as diagnostic marker for Alzheimer disease. Furthermore, it has to be determined whether the association of golgin A4 with GVBs is an epiphenomenon or whether golgin A4 plays a more direct role in Alzheimer disease, allowing it to serve as a target in therapeutic treatment strategies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that elevated CSFgolgin A4 levels identify patients with Alzheimer disease.
Authors: Stefan J Schunk; Juliane Hermann; Tamim Sarakpi; Sarah Triem; Michaela Lellig; Eunsil Hahm; Stephen Zewinger; David Schmit; Ellen Becker; Julia Möllmann; Michael Lehrke; Rafael Kramann; Peter Boor; Peter Lipp; Ulrich Laufs; Winfried März; Jochen Reiser; Joachim Jankowski; Danilo Fliser; Thimoteus Speer; Vera Jankowski Journal: J Am Soc Nephrol Date: 2021-09-29 Impact factor: 10.121
Authors: Setareh Orth-Alampour; Nathalie Gayrard; Silvia Salem; Àngel Argilés; Joachim Jankowski; Shruti Bhargava; Vera Jankowski; Bernard Jover; Cécile Notarnicola; Heidi Noels; Emiel P C van der Vorst; Christoph Kuppe; Michael Wolf; Claudia Goettsch; Wendy Theelen; Heike Bruck; Danilo Fliser; Joseph Loscalzo; Zhuojun Wu; Nikolaus Marx; Walter Zidek Journal: Basic Res Cardiol Date: 2021-10-13 Impact factor: 17.165