PMID- 31804189 OWN - NLM STAT- MEDLINE DCOM- 20201023 LR - 20201023 IS - 1945-4589 (Electronic) IS - 1945-4589 (Linking) VI - 11 IP - 23 DP - 2019 Dec 4 TI - Pharmacological inhibition of G9a/GLP restores cognition and reduces oxidative stress, neuroinflammation and beta-Amyloid plaques in an early-onset Alzheimer's disease mouse model. PG - 11591-11608 LID - 10.18632/aging.102558 [doi] AB - 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-alpha) 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 beta-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. FAU - Grinan-Ferre, Christian AU - Grinan-Ferre C AD - Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona 08028, Spain. FAU - Marsal-Garcia, Laura AU - Marsal-Garcia L AD - Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona 08028, Spain. FAU - Bellver-Sanchis, Aina AU - Bellver-Sanchis A AD - Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona 08028, Spain. FAU - Kondengaden, Shukkoor Muhammed AU - Kondengaden SM AD - Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA. FAU - Turga, Ravi Chakra AU - Turga RC AD - Department of Biology, Georgia State University, Atlanta, GA 30303, USA. FAU - Vazquez, Santiago AU - Vazquez S AD - Laboratori de Quimica Farmaceutica (Unitat Associada al CSIC), Department de Farmacologia, Toxicologia i Quimica Terapeutica, Facultat de Farmacia i Ciencies de l'Alimentacio, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Barcelona E-08028, Spain. FAU - Pallas, Merce AU - Pallas M AD - Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona 08028, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191204 PL - United States TA - Aging (Albany NY) JT - Aging JID - 101508617 RN - 0 (Amyloid beta-Peptides) RN - 0 (Histones) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Quinazolines) RN - 0 (UNC0642) RN - 62340-29-8 (Glucagon-Like Peptides) RN - EC 2.1.1.43 (G9a protein, mouse) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) SB - IM MH - Alzheimer Disease/*drug therapy MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Cognition/*drug effects MH - Cognitive Dysfunction/drug therapy MH - Gene Expression Regulation/drug effects MH - Glucagon-Like Peptides/*antagonists & inhibitors MH - Hippocampus MH - Histone-Lysine N-Methyltransferase/*antagonists & inhibitors MH - Histones/metabolism MH - Inflammation/drug therapy MH - Male MH - Mice MH - NF-E2-Related Factor 2/genetics/metabolism MH - Oxidative Stress/*drug effects MH - Quinazolines/*therapeutic use PMC - PMC6932909 OTO - NOTNLM OT - G9a/GLP OT - epigenetics OT - neuroinflammation OT - synaptic plasticity OT - beta-amyloid plaques COIS- CONFLICTS OF INTEREST: The authors have no conflicts of interests to declare. EDAT- 2019/12/06 06:00 MHDA- 2020/10/24 06:00 PMCR- 2019/12/15 CRDT- 2019/12/06 06:00 PHST- 2019/10/01 00:00 [received] PHST- 2019/11/20 00:00 [accepted] PHST- 2019/12/06 06:00 [pubmed] PHST- 2020/10/24 06:00 [medline] PHST- 2019/12/06 06:00 [entrez] PHST- 2019/12/15 00:00 [pmc-release] AID - 102558 [pii] AID - 10.18632/aging.102558 [doi] PST - ppublish SO - Aging (Albany NY). 2019 Dec 4;11(23):11591-11608. doi: 10.18632/aging.102558. Epub 2019 Dec 4.