title: TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer's disease hippocampus.
abstract: BACKGROUND
  Recent genome-wide association studies revealed TREM2 rs75932628-T variant to be associated with Alzheimer's disease (AD) and other neurodegenerative diseases. However, the role that TREM2 plays in sporadic AD is largely unknown. Our aim was to assess messenger RNA (mRNA) expression levels and DNA methylation profiling of TREM2 in human hippocampus in AD brain. We measured TREM2 mRNA levels in the hippocampus in a cohort of neuropathologically confirmed controls and pure AD cases showing no other protein deposits than β-amyloid and phosphorylated tau. We also examined DNA methylation levels in the TREM2 transcription start site (TSS)-associated region by bisulfite cloning sequencing and further extended the study by measuring 5-hydroxymethycytosine (5hmC) enrichment at different regions of TREM2 by 5hmC DNA immunoprecipitation combined with real-time qPCR.
  
  
  RESULTS
  A 3.4-fold increase in TREM2 mRNA levels was observed in the hippocampus of AD cases compared to controls (p = 1.1E-05). Interestingly, TREM2 methylation was higher in AD cases compared to controls (76.2 % ± 15.5 versus 57.9 % ± 17.1; p = 0.0016). Moreover, TREM2 mRNA levels in the AD hippocampus correlated with enrichment in 5hmC at the TREM2 gene body (r = 0.771; p = 0.005).
  
  
  CONCLUSIONS
  TREM2 mRNA levels are increased in the human hippocampus in AD cases compared to controls. DNA methylation, and particularly 5hmC, may be involved in regulating TREM2 mRNA expression in the AD brain. Further studies are guaranteed to investigate in depth the role of 5hmC in AD and other neurodegenerative disorders.
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed-Navarra Institute for Health Research (IdiSNA), c/ Irunlarrea, Pamplona, Navarra 31008 Spain.
authors.forename: Naiara
authors.initials: N
authors.lastname: Celarain
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed-Navarra Institute for Health Research (IdiSNA), c/ Irunlarrea, Pamplona, Navarra 31008 Spain ; Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra 31008 Spain ; Present address: Clínica San Miguel, Pamplona, Navarra 31006 Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Sánchez-Ruiz de Gordoa
authors.affiliation: Department of Pathology, Complejo Hospitalario de Navarra, Pamplona, Navarra 31008 Spain.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Zelaya
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed-Navarra Institute for Health Research (IdiSNA), c/ Irunlarrea, Pamplona, Navarra 31008 Spain.
authors.forename: Miren
authors.initials: M
authors.lastname: Roldán
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed-Navarra Institute for Health Research (IdiSNA), c/ Irunlarrea, Pamplona, Navarra 31008 Spain ; Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra 31008 Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Larumbe
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed-Navarra Institute for Health Research (IdiSNA), c/ Irunlarrea, Pamplona, Navarra 31008 Spain ; Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra 31008 Spain ; Present address: Clínica San Miguel, Pamplona, Navarra 31006 Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Pulido
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed-Navarra Institute for Health Research (IdiSNA), c/ Irunlarrea, Pamplona, Navarra 31008 Spain ; Hospital Psicogeriátrico Josefina Arregui, Alsasua, Navarra 31800 Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Echavarri
authors.affiliation: Neuroepigenetics Laboratory, Navarrabiomed-Navarra Institute for Health Research (IdiSNA), c/ Irunlarrea, Pamplona, Navarra 31008 Spain ; Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Navarra 31008 Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Mendioroz
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine
keywords: 5-Hydroxymethycytosine; Alzheimer’s disease; DNA methylation; Epigenetics; Gene expression; TREM2