Abstract
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.
Highlights
Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and its most significant factor is advanced age [1]
Novel Object Recognition Test (NORT) analysis demonstrated that 5XFAD treated with UNC0642 mice exhibited significantly reduced cognitive deficits in both short- and www.aging-us.com long-term memory presented by 5XFAD Control mice group (Figure 1D and 1E)
We confirmed the cognitive impairment of the 5XFAD mouse model in both short- and long-term memories compared to the Wt Control mice group (Figure 1D and 1E)
Summary
Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and its most significant factor is advanced age [1]. AD is characterized by the presence of extracellular senile or β-amyloid (Aβ) plaques and, intraneuronal neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau aggregates; and by neuronal death [2, 3]. Aβ plaques could contribute to NFTs, neuroinflammation, oxidative damage, and changes in chromatin structure [7, 8]. Some critical events known in AD are oxidative stress (OS), synaptic loss and glial responses as neuroinflammation [9]. Regarding OS, it may damage the nervous system and lead to synaptic dysfunction [10] and is relevant in neurodegenerative diseases as AD [11]. In the inflammation process, some cytokines produce neuronal damage and a higher expression and changes in Amyloid precursor protein (APP) processing of [12]. Tumor Necrosis Factor-alpha (TNF-α) and Interleukin 6 (IL-6) have been detected to aggravate both Aβ and tau pathologies in AD [13]
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