Pharmacological inhibition of G9a/GLP restores cognition and reduces oxidative stress, neuroinflammation and β-Amyloid plaques in an early-onset Alzheimer’s disease mouse model
02-13-2020UNC0642, a specific and potent inhibitor of methyltransferase activity G9a/GLP complex, was evaluated in the 5XFAD mouse model.
UNC0642 treatment rescued 5XFAD cognition impairment, reduced DNA-methylation, increased hydroxymethylation, and decreased the di-methylation of lysine 9 of histone H3 levels in the hippocampus.
An increase in Nerve growth factor, Nerve growth factor inducible gene expression, Brain-derived neurotrophic factor, and Synaptophysin were found after UNC0642 treatment.
Dr. Mercè Pallàs from the Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences at the Institute of Neuroscience, in the University of Barcelona (NeuroUB) said, "Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and its most significant factor is advanced age."
"Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and its most significant factor is advanced age."
- Dr. Mercè Pallàs, Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences at the Institute of Neuroscience, in the University of Barcelona (NeuroUB)
Various mechanisms, such as DNA methylation, hydroxymethylation, histone modifications, and regulation of the non-coding RNA, regulate the accessibility of chromatin to transcription factors and, therefore, these modifications are implicated in the modulation of DNA replication, transcription, and repair.
Consequently, its dysregulation is closely related to cognitive decline in aging and transcriptional changes in various neurogenerative diseases such as AD, Huntingtons disease and Amyotrophic lateral sclerosis.
Figure 7. Scheme of epigenetic and molecular mechanisms changed in 5XFAD mice induced by pharmacological inhibition of G9a/GLP by UNC0642 "Created with BioRender.com" (A).
Those epigenetic modifications lead to transcription repression.
Of note, the critical role of epigenetics in 5XFAD was revealed in a recent study, including a correlation among cognitive impairment, A pathology, and epigenetic modifications.
The present work aimed to evaluate the beneficial effects of the pharmacological inhibition activity of G9a/GLP with UNC0642 in 5XFAD mice, evaluating epigenetic changes, cognitive improvement, and the influence of the G9a/GLP complex inhibition in amyloid pathology, OS, neuroinflammation, and neuronal plasticity.
The Pallàs Research Team concluded, "our results provide new evidence that inhibition G9a/GLP activity might be a promising target for AD therapy (Figure 7)."
Full Text - https://doi.org/10.18632/aging.102558
Correspondence to: Mercè Pallàs email: pallas@ub.edu
Keywords: G9a/GLP, epigenetics, neuroinflammation, synaptic plasticity, β-amyloid plaques
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