title: sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers.
abstract: TREM2 is an innate immune receptor expressed on the surface of microglia. Loss-of-function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type-1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross-sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non-AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho-tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.
authors.affiliation: BioMedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Suárez-Calvet
authors.affiliation: BioMedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Araque Caballero
authors.affiliation: Department of Nuclear Medicine, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Brendel
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Department of Nuclear Medicine, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Rominger
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona, Barcelona, Spain Center for Networked Biomedical Research for Neurodegenerative Diseases, CIBERNED, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alcolea
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona, Barcelona, Spain Center for Networked Biomedical Research for Neurodegenerative Diseases, CIBERNED, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Fortea
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona, Barcelona, Spain Center for Networked Biomedical Research for Neurodegenerative Diseases, CIBERNED, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona, Barcelona, Spain Center for Networked Biomedical Research for Neurodegenerative Diseases, CIBERNED, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Blesa
authors.affiliation: Clinical and Neuroimaging Departments, Barcelona Beta Brain Research Center Pasqual Maragall Foundation, Barcelona, Spain Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.
authors.forename: Juan Domingo
authors.initials: JD
authors.lastname: Gispert
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Valle
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Antonell
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Rami
authors.affiliation: Clinical and Neuroimaging Departments, Barcelona Beta Brain Research Center Pasqual Maragall Foundation, Barcelona, Spain Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Frederic
authors.initials: F
authors.lastname: Brosseron
authors.affiliation: Neurology Department, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Traschütz
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Neurology Department, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge University of Antwerp, Antwerp, Belgium Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Hanne
authors.initials: H
authors.lastname: Struyfs
authors.affiliation: Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge University of Antwerp, Antwerp, Belgium Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium Laboratory of Neurogenetics, Institute Born-Bunge University of Antwerp, Antwerp, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium Laboratory of Neurogenetics, Institute Born-Bunge University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.affiliation: Clinical Neurochemistry Lab, Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden Reta Lila Weston Laboratories and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Department of Anaesthesiology and Intensive Care, Institute of Clinical Sciences Sahlgrenska Academy Gothenburg University, Gothenburg, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Nellgård
authors.affiliation: Clinical Neurochemistry Lab, Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Institute of Medical Informatics, Biometry, and Epidemiology, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Crispin
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany michael.ewers@med.uni-muenchen.de christian.haass@mail03.med.uni-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Ewers
authors.affiliation: BioMedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany michael.ewers@med.uni-muenchen.de christian.haass@mail03.med.uni-muenchen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000473:pathology*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D002555:Cerebrospinal Fluid / Q000737:chemistry; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000134:cerebrospinal fluid*; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D011971:Receptors, Immunologic
chemical_list: D015415:Biomarkers; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer's disease; TREM2; biomarkers; microglia; neurodegeneration