title: Increased Acetylation of Histone H4 at Lysine 12 (H4K12) in Monocytes of Transgenic Alzheimer's Mice and in Human Patients.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaque formation, tau pathology, neurodegeneration and inflammatory processes. Monocytes are involved in inflammation in AD and are recruited to the diseased brain. Recently it has been shown that aberrant epigenetic processes including acetylation are associated with the development of AD. The aim of the present study was to examine acetylation of histone H4 at lysine 12 (H4K12) in monocytes in two transgenic AD mouse models (the triple transgenic 3xTg and a model overexpressing amyloid-precursor protein APP with the Swedish-Dutch-Iowa mutations), and to compare with monocytes isolated from human patients with mild cognitive impairment (MCI) and AD.
  
  
  METHODS
  Mouse and human monocytes were selectively isolated with a positive (PluriSelect) respectively with a negative selection method (Miltenyi). Histones were extracted and acetylation of H4K12 was analyzed by a quantification fluorometric kit. Moreover, monocyte cytokine release was measured and cell death analyzed by FACS using incorporation of 7-AAD.
  
  
  RESULTS
  Our data show a significant increase of monocytic H4K12 acetylation in both transgenic AD mouse models early during development of the plaque deposition in the brain. In line with these data we found significantly elevated acetylation of H4K12 in human patients with MCI but not in patients with AD. Further we observed that the monocytes of AD mice and of AD patients were significantly more vulnerable to cell damage (as seen by 7-AAD incorporation in FACS analysis) and displayed an enhanced release of pro-inflammatory cytokines (MIP2 and TNFα).
  
  
  CONCLUSIONS
  Our findings indicate that epigenetic changes in peripheral monocytes are an early event in AD-pathology. Thus H4K12 acetylation may be considered as a novel biomarker for early changes in AD development.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plagg
authors.forename: Daniela
authors.initials: D
authors.lastname: Ehrlich
authors.forename: Kathrin M
authors.initials: KM
authors.lastname: Kniewallner
authors.forename: Josef
authors.initials: J
authors.lastname: Marksteiner
authors.affiliation: Department of Psychiatry and Psychotherapy, Anichstr. 35, A-6020 Innsbruck, Austria. christian.humpel@i-med.ac.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Humpel
mesh_terms: D000107:Acetylation; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death / Q000235:genetics; D060825:Cognitive Dysfunction / Q000235:genetics / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000201:enzymology*; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D006657:Histones; D053764:Presenilin-1; D016875:tau Proteins; D008239:Lysine