sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers

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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‐tau _181P, 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.

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Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer’s Disease: a Comparative Overview

Frederic Brosseron, Marius Krauthausen, Markus P Kummer … (2014)

This article gives a comprehensive overview of cytokine and other inflammation associated protein levels in plasma, serum and cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). We reviewed 118 research articles published between 1989 and 2013 to compare the reported levels of 66 cytokines and other proteins related to regulation and signaling in inflammation in the blood or CSF obtained from MCI and AD patients. Several cytokines are evidently regulated in (neuro-) inflammatory processes associated with neurodegenerative disorders. Others do not display changes in the blood or CSF during disease progression. However, many reports on cytokine levels in MCI or AD are controversial or inconclusive, particularly those which provide data on frequently investigated cytokines like tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6). The levels of several cytokines are possible indicators of neuroinflammation in AD. Some of them might increase steadily during disease progression or temporarily at the time of MCI to AD conversion. Furthermore, elevated body fluid cytokine levels may correlate with an increased risk of conversion from MCI to AD. Yet, research results are conflicting. To overcome interindividual variances and to obtain a more definite description of cytokine regulation and function in neurodegeneration, a high degree of methodical standardization and patients collective characterization, together with longitudinal sampling over years is essential. Electronic supplementary material The online version of this article (doi:10.1007/s12035-014-8657-1) contains supplementary material, which is available to authorized users.

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A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia.

Jennifer L. Hsieh, Eréne C. Niemi, Kouichi C. Nakamura … (2009)

Following neuronal injury, microglia initiate repair by phagocytosing dead neurons without eliciting inflammation. Prior evidence indicates triggering receptor expressed by myeloid cells-2 (TREM2) promotes phagocytosis and retards inflammation. However, evidence that microglia and neurons directly interact through TREM2 to orchestrate microglial function is lacking. We here demonstrate that TREM2 interacts with endogenous ligands on neurons. Staining with TREM2-Fc identified TREM2 ligands (TREM2-L) on Neuro2A cells and on cultured cortical and dopamine neurons. Apoptosis greatly increased the expression of TREM2-L. Furthermore, apoptotic neurons stimulated TREM2 signaling, and an anti-TREM2 mAb blocked stimulation. To examine the interaction between TREM2 and TREM2-L in phagocytosis, we studied BV2 microglial cells and their engulfment of apoptotic Neuro2A. One of our anti-TREM2 mAb, but not others, reduced engulfment, suggesting the presence of a functional site on TREM2 interacting with neurons. Further, Chinese hamster ovary cells transfected with TREM2 conferred phagocytic activity of neuronal cells demonstrating that TREM2 is both required and sufficient for competent uptake of apoptotic neuronal cells. Finally, while TREM2-L are expressed on neurons, TREM2 is not; in the brain, it is found on microglia. TREM2 and TREM2-L form a receptor-ligand pair connecting microglia with apoptotic neurons, directing removal of damaged cells to allow repair.

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A Dap12-Mediated Pathway Regulates Expression of Cc Chemokine Receptor 7 and Maturation of Human Dendritic Cells

Axel Bouchon, Cristina Hernández-Munain, Marina Cella … (2001)

Gene targeting of the adaptor molecule DAP12 in mice caused abnormal distribution and impaired antigen presentation capacity of dendritic cells (DCs). However, the DAP12-associated receptors expressed on DCs and their functions have not been identified yet. Here we show that the triggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor on human monocyte-derived DCs, which is associated with DAP12. TREM-2/DAP12 promotes upregulation of CC chemokine receptor 7, partial DC maturation, and DC survival through activation of protein tyrosine kinases and extracellular signal–regulated kinase. In contrast to Toll-like receptor-mediated signaling, TREM2/DAP12 stimulation is independent of nuclear factor-κB and p38 stress-activated protein kinase. This novel DC activation pathway may regulate DC homeostasis and amplify DC responses to pathogens, explaining the phenotype observed in DAP12-deficient mice.

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Author and article information

Journal

Journal ID (nlm-ta): EMBO Mol Med

Journal ID (iso-abbrev): EMBO Mol Med

Journal ID (doi): 10.1002/(ISSN)1757-4684

Journal ID (publisher-id): EMMM

Journal ID (hwp): embomm

Title: EMBO Molecular Medicine

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1757-4676

ISSN (Electronic): 1757-4684

Publication date (Electronic): 03 March 2016

Publication date (Print): May 2016

Volume: 8

Issue: 5 ( doiID: 10.1002/emmm.v8.5 )

Pages: 466-476

Affiliations

[ ¹ ] BioMedical Center (BMC), BiochemistryLudwig‐Maximilians‐University Munich MunichGermany

[ ² ]German Center for Neurodegenerative Diseases (DZNE) Munich MunichGermany

[ ³ ]Munich Cluster for Systems Neurology (SyNergy) MunichGermany

[ ⁴ ] Institute for Stroke and Dementia Research Klinikum der Universität MünchenLudwig‐Maximilians‐University Munich MunichGermany

[ ⁵ ] Department of Nuclear Medicine Klinikum der Universität MünchenLudwig‐Maximilians‐University Munich MunichGermany

[ ⁶ ] Department of NeurologyInstitut d'Investigacions Biomèdiques Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona BarcelonaSpain

[ ⁷ ] Center for Networked Biomedical Research for Neurodegenerative DiseasesCIBERNED MadridSpain

[ ⁸ ] Clinical and Neuroimaging DepartmentsBarcelona Beta Brain Research Center Pasqual Maragall Foundation BarcelonaSpain

[ ⁹ ] Centro de Investigación Biomédica en Red de BioingenieríaBiomateriales y Nanomedicina (CIBER‐BBN) BarcelonaSpain

[ ¹⁰ ] Alzheimer's Disease and Other Cognitive Disorders Unit Neurology ServiceICN Hospital Clinic i Universitari BarcelonaSpain

[ ¹¹ ]Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) BarcelonaSpain

[ ¹² ]German Center for Neurodegenerative Diseases (DZNE) BonnGermany

[ ¹³ ] Neurology DepartmentUniversitätsklinikum Bonn BonnGermany

[ ¹⁴ ] Reference Center for Biological Markers of Dementia (BIODEM) Laboratory of Neurochemistry and BehaviorInstitute Born‐Bunge University of Antwerp AntwerpBelgium

[ ¹⁵ ] Department of Neurology and Memory ClinicHospital Network Antwerp (ZNA) Middelheim and Hoge Beuken AntwerpBelgium

[ ¹⁶ ] Neurodegenerative Brain Diseases Group Department of Molecular GeneticsVIB AntwerpBelgium

[ ¹⁷ ] Laboratory of NeurogeneticsInstitute Born‐Bunge University of Antwerp AntwerpBelgium

[ ¹⁸ ] Clinical Neurochemistry LabInstitute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg MölndalSweden

[ ¹⁹ ] Reta Lila Weston Laboratories and Department of Molecular NeuroscienceUCL Institute of Neurology LondonUK

[ ²⁰ ] Department of Anaesthesiology and Intensive CareInstitute of Clinical Sciences Sahlgrenska Academy Gothenburg University GothenburgSweden

[ ²¹ ]Institute of Medical Informatics, Biometry, and Epidemiology MunichGermany

Author notes

[*] [* ] Corresponding author. Tel: +49 89 4400 46221; Fax: +49 89 4400 46113; E‐mail: michael.ewers@ 123456med.uni-muenchen.de

Corresponding author. Tel: +49 89 4400 46549; Fax: +49 89 4400 46546; E‐mail: christian.haass@ 123456mail03.med.uni-muenchen.de

[†]

These authors contributed equally to this study

Article

Publisher ID: EMMM201506123

DOI: 10.15252/emmm.201506123

PMC ID: 5120370

PubMed ID: 26941262

SO-VID: 05904976-5471-44e8-9337-94b11e1e97b6

License:

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 03 December 2015

Date revision received : 27 January 2016

Date accepted : 28 January 2016

Page count

Pages: 11

Funding

Funded by: European Commission

Award ID: PCIG12‐GA‐2012‐334259

Funded by: European Research Council

Award ID: FP7/2007–2013

Award ID: 321366

Funded by: Deutsche Forschungsgemeinschaft (German Research Foundation)

Award ID: 115372

Funded by: Cure Alzheimer's Fund

Funded by: MetLife Foundation Award

Funded by: Swedish Research Council

Funded by: Torsten Söderberg Foundation

Funded by: Royal Swedish Academy of Sciences

Funded by: Knut and Alice Wallenberg Foundation

Funded by: Frimurarestiftelsen

Award ID: 115372

Funded by: University Research Fund of the University of Antwerp

Funded by: Institute Born‐Bunge

Funded by: Foundation for Alzheimer Research (SAO‐FRA)

Funded by: Neurosearch Antwerp

Funded by: Research Foundation—Flanders (FWO)

Funded by: Agency for Innovation by Science and Technology (IWT)

Funded by: Interuniversity Attraction Poles (IAP) Program of the Belgian Science Policy Office

Funded by: Flemish Government Methusalem Excellence Program, Belgium

Funded by: Flanders Impulse Program on Networks for Dementia Research (VIND)

Funded by: EU Joint Program for Neurodegenerative Disease Research (JPND)

Award ID: 321366

Funded by: EU/EFPIA Innovative Medicines Initiative Joint Undertaking

Award ID: 115372

Funded by: Belgian Science Policy Office Interuniversity Attraction Poles Program

Funded by: Flanders Government Initiated Impulse Program on Networks for Dementia Research (VIND)

Funded by: Flemish government Initiated Methusalem Excellence Program

Funded by: University of Antwerp Research Fund, Belgium

Funded by: Janssen

Funded by: ADx Neurosciences

Funded by: Innogenetics/Fujirebio Europe

Funded by: Lundbeck

Funded by: Pfizer

Award ID: 115372

Funded by: Novartis

Funded by: UCB

Funded by: Roche Diagnostics

Funded by: Nutricia/Danone

Award ID: 115372

Custom metadata

source-schema-version-number 2.0

component-id emmm201506123

cover-date May 2016

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.7 mode:remove_FC converted:18.11.2016

ScienceOpen disciplines: Molecular medicine

Keywords: alzheimer's disease,biomarkers,microglia,neurodegeneration,trem2,biomarkers & diagnostic imaging,neuroscience

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: alzheimer's disease, biomarkers, microglia, neurodegeneration, trem2, biomarkers & diagnostic imaging, neuroscience

sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers

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Abstract

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Neuronal Signaling

Most cited references 20

Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer’s Disease: a Comparative Overview

A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia.

A Dap12-Mediated Pathway Regulates Expression of Cc Chemokine Receptor 7 and Maturation of Human Dendritic Cells

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