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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Yuetiva Deming
  • Fabia Filipello
  • Francesca Cignarella
  • Claudia Cantoni
  • Simon Hsu
  • Robert Mikesell
  • Zeran Li
  • Jorge L. Del-Aguila
  • Umber Dube
  • Fabiana Geraldo Farias
  • Joseph Bradley
  • John Budde
  • Laura Ibanez
  • Maria Victoria Fernandez
  • Kaj Blennow
  • Henrik Zetterberg
  • Amanda Heslegrave
  • Bengt Nellgård
  • Alberto Lleo
  • Daniel Alcolea
  • Jordi Clarimon
  • Lorena Rami
  • José Luis Molinuevo
  • Marc Suárez-Calvet
  • Estrella Morenas-Rodríguez
  • Gernot Kleinberger
  • Michael Ewers
  • Oscar Harari
  • Christian Haass
  • Thomas J. Brett
  • Bruno A. Benitez
  • Celeste M. Karch
  • Laura Piccio
  • Carlos Cruchaga
Enheter & grupper
Externa organisationer
  • Washington University in St. Louis
  • University of Wisconsin-Madison
  • Sahlgrenska Academy
  • Sahlgrenska University Hospital
  • University College London
  • Autonomous University of Barcelona
  • CIBER Enfermedades Neurodegenerativas (CIBERNED)
  • Hospital Clínic of Barcelona
  • Pasqual Maragall Foundation for Research on Alzheimer
  • German Center for Neurodegenerative Diseases
  • Munich Cluster for Systems Neurology
  • University of Sydney
  • Ludwig-Maximilian University of Munich
  • ISAR Bioscience GmbH
  • University Hospital Munich
  • World Orthopaedic Concern
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Originalspråkengelska
Artikelnummereaau2291
TidskriftScience Translational Medicine
Volym11
Utgivningsnummer505
StatusPublished - 2019 aug 14
PublikationskategoriForskning
Peer review utfördJa