转基因的阿尔茨海默证小鼠单核细胞和人类患者中H4组蛋白赖氨酸12乙酰化增加

Title:Increased Acetylation of Histone H4 at Lysine 12 (H4K12) in Monocytes of Transgenic Alzheimer’s Mice and in Human Patients

Volume: 12 Issue: 8

Author(s): Barbara Plagg, Daniela Ehrlich, Kathrin M Kniewallner, and Josef Marksteiner

Affiliation:

关键词: 乙酰化，阿尔茨海默病，表观遗传学，H4K12，组蛋白，MCI，单核细胞。

摘要: 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). Conclusion: 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.

Cite this article as:

Plagg Barbara, Ehrlich Daniela, Kniewallner, M Kathrin and Marksteiner Josef, Increased Acetylation of Histone H4 at Lysine 12 (H4K12) in Monocytes of Transgenic Alzheimer’s Mice and in Human Patients, Current Alzheimer Research 2015; 12 (8) . https://dx.doi.org/10.2174/1567205012666150710114256