Open AccessPharmacological inhibition of G9a/GLP restores cognition and reduces oxidative stress, neuroinflammation and β-Amyloid plaques in an early-onset Alzheimer’s disease mouse model
Author(s) -
Christian GriñánFerré,
Laura Marsal-García,
Aina Bellver-Sanchis,
Shukkoor Muhammed Kondengaden,
Ravi Chakra Turga,
Santiago Vázquez,
Mercè Pallàs
Publication year - 2019
Publication title -
aging
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.473
H-Index - 90
ISSN - 1945-4589
DOI - 10.18632/aging.102558
Subject(s) - neuroinflammation , synaptophysin , neurotrophic factors , nerve growth factor , oxidative stress , brain derived neurotrophic factor , neuroprotection , glial fibrillary acidic protein , heme oxygenase , amyloid precursor protein , amyloid beta , endocrinology , neurotrophin , biology , medicine , alzheimer's disease , neuroscience , heme , inflammation , biochemistry , receptor , disease , immunohistochemistry , enzyme
The implication of epigenetic mechanisms in Alzheimer’s disease (AD) has been demonstrated in several studies. UNC0642, a specific and potent inhibitor of methyltransferase activity G9a/GLP (G9a-like) complex, was evaluated in the 5XFAD mouse model. UNC0642 treatment rescued 5XFAD cognition impairment, reduced DNA-methylation (5-mC), increased hydroxymethylation (5-hmC), and decreased the di-methylation of lysine 9 of histone H3 (H3K9me2) levels in the hippocampus. Increases in the Nuclear Factor erythroid-2-Related Factor 2 (NRF2), Heme oxygenase decycling 1 ( Hmox1) gene expression, and diminution in Reactive Oxygen Species (ROS) were also reported. Moreover, neuroinflammatory markers, such as Interleukin 6 ( Il-6), Tumor necrosis factor-alpha (Tnf-α ) gene expression, and Glial fibrillary acidic protein (GFAP) immunofluorescence were reduced by UNC0642 treatment. An increase in Nerve growth factor (Ngf), Nerve growth factor inducible (Vgf) gene expression, Brain-derived neurotrophic factor (BDNF), and Synaptophysin (SYN) were found after UNC0642 treatment. Importantly, a reduction in β-amyloid plaques was also observed. In conclusion, our work demonstrates that the inhibition of the G9a/GLP complex by UNC0642 delivered significant neuroprotective effects in 5XFAD mice, point out G9a/GLP as a new target for AD.