Julia Remnestål1, Sofia Bergström1, Jennie Olofsson1, Evelina Sjöstedt1,2, Mathias Uhlén1,2, Kaj Blennow3,4, Henrik Zetterberg3,4,5,6, Anna Zettergren3,7, Silke Kern3,7,8, Ingmar Skoog3,7,8, Peter Nilsson1, Anna Månberg9. 1. Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden. 2. Department of Neuroscience, Karolinska Institutet, Solna, Sweden. 3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 4. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 5. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. 6. UK Dementia Research Institute at UCL, London, UK. 7. Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden. 8. Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden. 9. Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden. anna.manberg@scilifelab.se.
Abstract
BACKGROUND: Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer's disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains. METHODS: In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. RESULTS: The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score. CONCLUSIONS: We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins' role in AD pathophysiology.
BACKGROUND: Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer's disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains. METHODS: In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. RESULTS: The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score. CONCLUSIONS: We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins' role in AD pathophysiology.
Authors: William T Hu; Alice Chen-Plotkin; Steven E Arnold; Murray Grossman; Christopher M Clark; Leslie M Shaw; Eve Pickering; Max Kuhn; Yu Chen; Leo McCluskey; Lauren Elman; Jason Karlawish; Howard I Hurtig; Andrew Siderowf; Virginia M-Y Lee; Holly Soares; John Q Trojanowski Journal: Acta Neuropathol Date: 2010-03-16 Impact factor: 17.088
Authors: Hlin Kvartsberg; Flora H Duits; Martin Ingelsson; Niels Andreasen; Annika Öhrfelt; Kerstin Andersson; Gunnar Brinkmalm; Lars Lannfelt; Lennart Minthon; Oskar Hansson; Ulf Andreasson; Charlotte E Teunissen; Philip Scheltens; Wiesje M Van der Flier; Henrik Zetterberg; Erik Portelius; Kaj Blennow Journal: Alzheimers Dement Date: 2014-12-19 Impact factor: 21.566
Authors: Alistair T Pagnamenta; Hameed Khan; Susan Walker; Dianne Gerrelli; Kirsty Wing; Maria Clara Bonaglia; Roberto Giorda; Tom Berney; Elisa Mani; Massimo Molteni; Dalila Pinto; Ann Le Couteur; Joachim Hallmayer; James S Sutcliffe; Peter Szatmari; Andrew D Paterson; Stephen W Scherer; Veronica J Vieland; Anthony P Monaco Journal: J Med Genet Date: 2010-10-23 Impact factor: 6.318
Authors: Julia Remnestål; David Just; Nicholas Mitsios; Claudia Fredolini; Jan Mulder; Jochen M Schwenk; Mathias Uhlén; Kim Kultima; Martin Ingelsson; Lena Kilander; Lars Lannfelt; Per Svenningsson; Bengt Nellgård; Henrik Zetterberg; Kaj Blennow; Peter Nilsson; Anna Häggmark-Månberg Journal: Proteomics Clin Appl Date: 2016-10-10 Impact factor: 3.494
Authors: Steffen Halbgebauer; Patrick Oeckl; Petra Steinacker; Deniz Yilmazer-Hanke; Sarah Anderl-Straub; Christine von Arnim; Lutz Froelich; Luis Aragão Gomes; Lucrezia Hausner; Andre Huss; Holger Jahn; Jochen Weishaupt; Albert C Ludolph; Dietmar R Thal; Markus Otto Journal: J Neurol Neurosurg Psychiatry Date: 2020-12-30 Impact factor: 10.154
Authors: Flora H Duits; Gunnar Brinkmalm; Charlotte E Teunissen; Ann Brinkmalm; Philip Scheltens; Wiesje M Van der Flier; Henrik Zetterberg; Kaj Blennow Journal: Alzheimers Res Ther Date: 2018-01-15 Impact factor: 6.982
Authors: Sofia Bergström; Linn Öijerstedt; Caroline Graff; Peter Nilsson; Julia Remnestål; Jennie Olofsson; Abbe Ullgren; Harro Seelaar; John C van Swieten; Matthis Synofzik; Raquel Sanchez-Valle; Fermin Moreno; Elizabeth Finger; Mario Masellis; Carmela Tartaglia; Rik Vandenberghe; Robert Laforce; Daniela Galimberti; Barbara Borroni; Chris R Butler; Alexander Gerhard; Simon Ducharme; Jonathan D Rohrer; Anna Månberg Journal: Mol Neurodegener Date: 2021-11-27 Impact factor: 14.195