The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk
Por:
Deming, Y, Filipello, F, Cignarella, F, Cantoni, C, Hsu, S, Mikesell, R, Li, ZR, Del-Aguila, JL, Dube, U, Farias, FG, Bradley, J, Budde, J, Ibanez, L, Fernandez, MV, Blennow, K, Zetterberg, H, Heslegrave, A, Johansson, PM, Svensson, J, Nellgard, B, Lleo, A, Alcolea, D, Clarimon, J, Rami, L, Molinuevo, JL, Suarez-Calvet, M, Morenas-Rodriguez, E, Kleinberger, G, Ewers, M, Harari, O, Haass, C, Brett, TJ, Benitez, BA, Karch, CM, Piccio, L, Cruchaga, C
Publicada:
14 ago 2019
Resumen:
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 x 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.
Filiaciones:
Deming, Y:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Univ Wisconsin, Sch Med & Publ Hlth, Alzheimers Dis Res Ctr, Madison, WI 53792 USA
Filipello, F:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Cignarella, F:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Cantoni, C:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Hsu, S:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Li, ZR:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Del-Aguila, JL:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Dube, U:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Farias, FG:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Bradley, J:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Budde, J:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Ibanez, L:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Fernandez, MV:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Blennow, K:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden
Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Neurosci & Physiol, Clin Neurochem Lab, Molndal, Sweden
Zetterberg, H:
Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Neurosci & Physiol, Clin Neurochem Lab, Molndal, Sweden
UCL Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London, England
Heslegrave, A:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden
UCL Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London, England
UCL, UK Dementia Res Inst, London, England
Johansson, PM:
Lund Univ, Dept Clin Sci Helsingborg, Lund, Sweden
Svensson, J:
Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, Gothenburg, Sweden
Nellgard, B:
Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med, Dept Anesthesiol,Sahlgrenska Univ Hosp,Inst Med, Gothenburg, Sweden
Lleo, A:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, IIB Sant Pau, Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, Spain
Alcolea, D:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, IIB Sant Pau, Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, Spain
Clarimon, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, IIB Sant Pau, Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, Spain
Rami, L:
ICN Hosp Clin, Neurol Serv, IDIBAPS, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Molinuevo, JL:
ICN Hosp Clin, Neurol Serv, IDIBAPS, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Pasqual Maragall Fdn, BarcelonaBeta Brain Res Ctr, Barcelona, Spain
Suarez-Calvet, M:
Pasqual Maragall Fdn, BarcelonaBeta Brain Res Ctr, Barcelona, Spain
Ludwig Maximilians Univ Munchen, Biochem, Biomed Ctr BMC, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Morenas-Rodriguez, E:
Ludwig Maximilians Univ Munchen, Biochem, Biomed Ctr BMC, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Kleinberger, G:
Ludwig Maximilians Univ Munchen, Biochem, Biomed Ctr BMC, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
ISAR Biosci GmbH, D-2152 Planegg, Germany
Ewers, M:
LMU, Univ Hosp, Inst Stroke & Dementia Res, Munich, Germany
Harari, O:
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Haass, C:
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Ludwig Maximilians Univ Munchen, Fac Med, Biomed Ctr BMC, Chair Metab Biochem, D-81377 Munich, Germany
Brett, TJ:
Washington Univ, Sch Med, Dept Internal Med, Div Pulm & Crit Care Med, St Louis, MO 63110 USA
Benitez, BA:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Karch, CM:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Piccio, L:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Univ Sydney, Brain & Mind Ctr, Sydney, NSW 2050, Australia
Cruchaga, C:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Bronze, Green Accepted
|