Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease

You Me Sung, Taehee Lee, Hyejin Yoon, Amanda Marie DiBattista, Jung Min Song, Yoojin Sohn, Emily Isabella Moffat, R. Scott Turner, Mira Jung, Jungsu Kim, Hyang Sook Hoe

Research output: Contribution to journalArticlepeer-review

114 Scopus citations


Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC. Given their ability to decrease Aβ levels, HDACIs are a potential treatment for Alzheimer's disease (AD). However, it is unclear how HDACIs alter Aβ levels. We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2) and investigated how they affect Aβ levels and cognition. HDACI W2 decreased Aβ40 and Aβ42 in vitro. HDACI I2 also decreased Aβ40, but not Aβ42. We systematically examined the molecular mechanisms by which HDACIs W2 and I2 can decrease Aβ levels. HDACI W2 decreased gene expression of γ-secretase components and increased the Aβ degradation enzyme Mmp2. Similarly, HDACI I2 decreased expression of β- and γ-secretase components and increased mRNA levels of Aβ degradation enzymes. HDACI W2 also significantly decreased Aβ levels and rescued learning and memory deficits in aged hAPP 3xTg AD mice. Furthermore, we found that the novel HDACI W2 decreased tau phosphorylation at Thr181, an effect previously unknown for HDACIs. Collectively, these data suggest that class II HDACls may serve as a novel therapeutic strategy for AD.

Original languageEnglish (US)
Pages (from-to)192-201
Number of pages10
JournalExperimental Neurology
Issue number1
StatePublished - Jan 2013

Bibliographical note

Funding Information:
This work is supported by NIH AG034253 (HSH), NIH AG039708 (HSH), M4M Recipient of Young investigator award (HSH), NIH AG026478 (RST), and P30NS069329 (JK). We are grateful to Dr. Hey-Kyoung Lee for helpful discussions on this project. We appreciate the generosity of Music for the Mind in funding this project. We also appreciate the generous gift of the N2a-APP stable cell line from Dr. Paul Matthews at New York University.


  • AD
  • APP
  • Alzheimer's disease
  • Amyloid precursor protein
  • Amyloid-β
  • Epigenetics
  • Histone deacetylase inhibitors


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