A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway
Abstract
BACKGROUND: The accumulation of amyloid-β (Aβ) leads to the loss of dendritic spines and synapses, which is hypothesized to cause cognitive impairments in Alzheimer's disease (AD) patients. In our previous study, we demonstrated that a novel mercaptoacetamide-based class II histone deacetylase inhibitor (HDACI), known as W2, decreased Aβ levels and improved learning and memory in mice. However, the underlying mechanism of this effect is unknown. OBJECTIVE: Because dendritic spine formation is associated with cognitive performance, here we investigated whether HDACI W2 regulates dendritic spine density and its molecular mechanism of action. METHODS: To examine the effect of HDACI W2 on dendritic spine density, we conducted morphological analysis of dendritic spines using GFP transfection and Golgi staining. In addition, to determine the molecular mechanism of W2 effects on spines, we measured the levels of mRNAs and proteins involved in the Ras signaling pathway using quantitative real-time PCR, immunocytochemistry, and western analysis. RESULTS: We found that HDACI W2 altered dendritic spine density and morphology in vitro and in vivo. Additionally, W2 increased the mRNA or protein levels of Ras GRF1 and phospho-ERK. Moreover, knockdown of RasGRF1 and inhibition of ERK activity prevented the W2-mediated spinogenesis in primary hippocampal neurons. CONCLUSION: Our Class II-selective HDACI W2 promotes the formation and growth of dendritic spines in a RasGRF1 and ERK dependent manner in primary hippocampal neurons.
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- Authors
- Song, J. M., Sung, Y. M., Nam, J. H., Yoon, H., Chung, A., Moffat, E., Jung, M., Pak, D. T. S., Kim, J., & Hoe, H.-S.
- Affiliations
- Georgetown University Medical Center (US)
- Korea Brain Research Institute (KR)
- Mayo Clinic (US)
- Corresponding author
- Kim, Jungsu
- Hoe, Hyang-Sook
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2016-03-15
- Volume
- 51
- Issue
- 2
- Pages
- 591-604
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2261326803
- Semantic Scholar
- 4e53baac21dc959180bf6a40df77b336945dab49
- Cited by
- 18
- References
- 35
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2021: 1 · 2020: 6 · 2018: 2 · 2017: 4
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, Davis
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- MeSH terms
- Acetamides, Animals, Cells, Cultured, Cerebral Cortex, Hippocampus, Immunohistochemistry, Mice, Inbred C57BL, RNA, Messenger, Thioglycolates, Transfection, Blotting, Western, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, AMPA, ras-GRF1, MAP Kinase Signaling System, Dendritic Spines, Green Fluorescent Proteins, Gene Knockdown Techniques, Histone Deacetylase Inhibitors, Real-Time Polymerase Chain Reaction
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