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Sci Transl Med. 2019 Aug 14;11(505). pii: eaau2291. doi: 10.1126/scitranslmed.aau2291.

The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk.

Author information

1
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
3
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
5
Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
6
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
7
UK Dementia Research Institute at UCL, London, UK.
8
Department of Clinical Sciences Helsingborg, Lund University, Lund, Sweden.
9
Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
10
Department of Anesthesiology, Sahlgrenska University Hospital, Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
11
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
12
Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
13
IDIBAPS, Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic, Barcelona, Spain.
14
Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
15
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
16
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
17
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
18
ISAR Bioscience GmbH, 2152 Planegg, Germany.
19
Institute for Stroke and Dementia Research, University Hospital, LMU, Munich, Germany.
20
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
21
NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO 63110, USA.
22
Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
23
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
24
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. karchc@wustl.edu picciol@wustl.edu ccruchaga@wustl.edu.
25
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. karchc@wustl.edu picciol@wustl.edu ccruchaga@wustl.edu.
26
Brain and Mind Centre, University of Sydney, Sydney, NSW 2050, Australia.

Abstract

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10-15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

PMID:
31413141
PMCID:
PMC6697053
[Available on 2020-08-14]
DOI:
10.1126/scitranslmed.aau2291

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