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Cited 14 time in webofscience Cited 14 time in scopus
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A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway

Authors
Song, Jung MinSung, You MeNam, Jin HanYoon, HyejinChung, AndrewMoffat, EmilyJung, MiraPak, Daniel T. S.Kim, JungsuHoe, Hyang-Sook
Issue Date
Dec-2016
Publisher
IOS PRESS
Keywords
Alzheimer' s disease; dendritic spine; HDAC inhibitor; ras signaling
Citation
JOURNAL OF ALZHEIMERS DISEASE, v.51, no.2, pp.591 - 604
Journal Title
JOURNAL OF ALZHEIMERS DISEASE
Volume
51
Number
2
Start Page
591
End Page
604
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/847
DOI
10.3233/JAD-150717
ISSN
1387-2877
Abstract
Background: The accumulation of amyloid-beta (A beta) 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 A beta 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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연구본부 (퇴행성뇌질환 연구그룹)
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