Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease.
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.
Department of Neuroscience, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057-1464, USA.
You Me
YM
Sung
Taehee
T
Lee
Hyejin
H
Yoon
Amanda Marie
AM
DiBattista
Jung Min
JM
Song
Yoojin
Y
Sohn
Emily Isabella
EI
Moffat
R Scott
RS
Turner
Mira
M
Jung
Jungsu
J
Kim
Hyang-Sook
HS
Hoe
D000081:Acetamides / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007858:Learning / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D009474:Neurons / Q000187:drug effects; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D013864:Thioglycolates / Q000494:pharmacology*; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism
D000081:Acetamides; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D056572:Histone Deacetylase Inhibitors; D013864:Thioglycolates; D016875:tau Proteins; D056464:Histone Deacetylase 2