Abstract
As a neurodegenerative disease, Alzheimer's disease (AD) seriously affects the health of older people. It is now known that changes in synapses occur first in the course of disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) can mediate the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects by using an HDACI, BG45 in Human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/Ps1 transgenic mice during this study. The cells were treated with 15µM BG45 and the APP/Ps1 mice 30mg/kg BG45. We detected the level of synapse-related proteins, HDACs, tau phosphorylation and AMPA receptors by western bloting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA level of GRIK2, SCN3B, SYNPR, Grm2, Grid2IP, GRIP1,GRIP2 were. to explore the effects of HDACi on regulating the synaptic proteins and AMPA receptors. Our studies demonstrated that the expression of HDAC1、HDAC2 and HDAC3 was increased, which was accompanied by the downregulation of the synapse-related proteins synaptophysin (SYP), postsynaptic dendritic protein (PSD-95) and spinophilin as early as 24 h after transfection with APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptotic loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau and increased the level of the synapse-related genes GRIK2, SCN3B, SYNPR, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2 and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. These results suggest that HDACs are involved in the early process of synaptic defects of AD and that BG45 may rescue synaptic damage and loss of hippocampal neurons by specifically inhibiting HDAC1、HDAC2 and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression and finally improving excitatory synapses. BG45 may be considered as a potential drug for the treatment of early AD for further study.