A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway
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....
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MDPI AG
2022-06-01
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| author | Ying Han Le Chen Jingyun Liu Jie Chen Chunyang Wang Yu Guo Xuebin Yu Chenghong Zhang Haiying Chu Haiying Ma |
| author_facet | Ying Han Le Chen Jingyun Liu Jie Chen Chunyang Wang Yu Guo Xuebin Yu Chenghong Zhang Haiying Chu Haiying Ma |
| author_sort | Ying Han |
| collection | DOAJ |
| description | 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. |
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| spelling | doaj.art-d750b832fd7c4edeabe0191c8e7aee782023-11-30T22:14:35ZengMDPI AGMolecules1420-30492022-06-012713416010.3390/molecules27134160A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA PathwayYing Han0Le Chen1Jingyun Liu2Jie Chen3Chunyang Wang4Yu Guo5Xuebin Yu6Chenghong Zhang7Haiying Chu8Haiying Ma9Department of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaDepartment of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, ChinaAs 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.https://www.mdpi.com/1420-3049/27/13/4160Alzheimer’s diseaseHDAC inhibitorβ-amyloidsynapseAMPA receptor |
| spellingShingle | Ying Han Le Chen Jingyun Liu Jie Chen Chunyang Wang Yu Guo Xuebin Yu Chenghong Zhang Haiying Chu Haiying Ma A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway Molecules Alzheimer’s disease HDAC inhibitor β-amyloid synapse AMPA receptor |
| title | A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway |
| title_full | A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway |
| title_fullStr | A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway |
| title_full_unstemmed | A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway |
| title_short | A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway |
| title_sort | class i hdac inhibitor rescues synaptic damage and neuron loss in app transfected cells and app ps1 mice through the grip1 ampa pathway |
| topic | Alzheimer’s disease HDAC inhibitor β-amyloid synapse AMPA receptor |
| url | https://www.mdpi.com/1420-3049/27/13/4160 |
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