As a neurodegenerative disease, Alzheimer’s disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) mediates the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the 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 15 μM BG45 and the APP/PS1 mice were treated with 30 mg/kg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, 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. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies.

BG45 is a class Ⅰ histone deacetylase inhibitor (HDACI) with selectivity for HDAC3. Our previous study demonstrated that BG45 can upregulate the expression of synaptic proteins and reduce the loss of neurons in the hippocampus of APPswe/PS1dE9 (APP/PS1) transgenic mice (Tg). The entorhinal cortex is a pivotal region that, along with the hippocampus, plays a critical role in memory in the Alzheimer’s disease (AD) pathology process. In this study, we focused on the inflammatory changes in the entorhinal cortex of APP/PS1 mice and further explored the therapeutic effects of BG45 on the pathologies. The APP/PS1 mice were randomly divided into the transgenic group without BG45 (Tg group) and the BG45-treated groups. The BG45-treated groups were treated with BG45 at 2 months (2 m group), at 6 months (6 m group), or twice at 2 and 6 months (2 and 6 m group). The wild-type mice group (Wt group) served as the control. All mice were killed within 24 h after the last injection at 6 months. The results showed that amyloid-β (Aβ) deposition and IBA1-positive microglia and GFAP-positive astrocytes in the entorhinal cortex of the APP/PS1 mice progressively increased over time from 3 to 8 months of age. When the APP/PS1 mice were treated with BG45, the level of H3K9K14/H3 acetylation was improved and the expression of histonedeacetylase1, histonedeacetylase2, and histonedeacetylase3 was inhibited, especially in the 2 and 6 m group. BG45 alleviated Aβ deposition and reduced the phosphorylation level of tau protein. The number of IBA1-positive microglia and GFAP-positive astrocytes decreased with BG45 treatment, and the effect was more significant in the 2 and 6 m group. Meanwhile, the expression of synaptic proteins synaptophysin, postsynaptic density protein 95, and spinophilin was upregulated and the degeneration of neurons was alleviated. Moreover, BG45 reduced the gene expression of inflammatory cytokines interleukin-1β and tumor necrosis factor-α. Closely related to the CREB/BDNF/NF-kB pathway, the expression of p-CREB/CREB, BDNF, and TrkB was increased in all BG45 administered groups compared with the Tg group. However, the levels of p-NF-kB/NF-kB in the BG45 treatment groups were reduced. Therefore, we deduced that BG45 is a potential drug for AD by alleviating inflammation and regulating the CREB/BDNF/NF-kB pathway, and the early, repeated administration of BG45 can play a more effective role.