A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway

Abstract

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.

Expression Analyses of Polo-Like Kinase 4, a Gene Product Responsible for Autosomal Recessive Microcephaly and Seckel Syndrome, during Mouse Brain Development

“…The staining patterns of Plk4 in the cerebral cortex and hippocampal CA1 (Fig. 2C, b, b’, c, and c’) resemble those of molecules distributed in neuropils, such as spinophilin [19], guanylate kinase-associated protein [20], p140Cap [21], and Wdr45 [22], suggesting the Plk4 localization at excitatory synapses. On the contrary, Plk4 was barely detected in axon bundles in the striatum (Fig.…”

Aging‐related histone modification changes in brain function

“…20 In contrast, inhibition of HDACs increased synaptic plasticity, increased the number of dendritic spines, and improved memory in young animals. 24 Specific inhibition of HDAC2 enhanced the acetylation of H3K9 and H3K14 at neuronal IEG promoters, restored their expression in the hippocampus of aged mice, and prevented memory impairment. 20 HDAC3 is a significant contributor to the decline in learning and memory.…”

“…Increased HDAC2 activity reduces the expression of neuronal IEGs by decreasing the acetylation of H3K9 and H3K14 at the promoters of these genes 20 . In contrast, inhibition of HDACs increased synaptic plasticity, increased the number of dendritic spines, and improved memory in young animals 24 . Specific inhibition of HDAC2 enhanced the acetylation of H3K9 and H3K14 at neuronal IEG promoters, restored their expression in the hippocampus of aged mice, and prevented memory impairment 20 …”

Selective HDAC6 inhibition protects against blood–brain barrier dysfunction after intracerebral hemorrhage

“…Histone deacetylase inhibitors (HDACis) have been found to act on stroke and neurodegenerative diseases via various mechanisms in recent years. 7 , 8 , 9 , 10 Pan‐ and isoform‐specific HDACis play roles in different cerebral diseases including hemorrhagic stroke. 11 HDAC6 belongs to the class IIb HDACs, mainly locates in cytoplasm and possesses two catalytic domains.…”

“…in recent years. [7][8][9][10] Pan-and isoform-specific HDACis play roles in different cerebral diseases including hemorrhagic stroke. 11 HDAC6 belongs to the class IIb HDACs, mainly locates in cytoplasm and possesses two catalytic domains.…”