Abstract
SummaryThe accumulation and deposition of beta‐amyloid (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Histone deacetylases (HDACs) are promising therapeutic targets for the treatment of AD, while the specific HDAC isoforms associated with cognitive improvement are poorly understood. In this study, we investigate the role of HDAC3 in the pathogenesis of AD. Nuclear HDAC3 is significantly increased in the hippocampus of 6‐ and 9‐month‐old APPswe/PS1dE9 (APP/PS1) mice compared with that in age‐matched wild‐type C57BL/6 (B6) mice. Lentivirus ‐mediated inhibition or overexpression of HDAC3 was used in the hippocampus of APP/PS1 mice to investigate the role of HDAC3 in spatial memory, amyloid burden, dendritic spine density, glial activation and tau phosphorylation. Inhibition of HDAC3 in the hippocampus attenuates spatial memory deficits, as indicated in the Morris water maze test, and decreases amyloid plaque load and Aβ levels in the brains of APP/PS1 mice. Dendritic spine density is increased, while microglial activation is alleviated after HDAC3 inhibition in the hippocampus of 9‐month‐old APP/PS1 mice. Furthermore, HDAC3 overexpression in the hippocampus increases Aβ levels, activates microglia, and decreases dendritic spine density in 6‐month‐old APP/PS1 mice. In conclusion, our results indicate that HDAC3 negatively regulates spatial memory in APP/PS1 mice and HDAC3 inhibition might represent a potential therapy for the treatment of AD.
Highlights
Alzheimer’s disease (AD), the most common cause of dementia among the elderly, is a progressive neurodegenerative disease that affects 5.3 million people in the United States (Alzheimer’s’s, 2015)
We investigated whether HDAC3 modulates spatial memory and pathogenesis in an AD mouse model
HDAC3 is increased in the hippocampal nuclei of APPswe/ PS1dE9 (APP/PS1) mice
Summary
Alzheimer’s disease (AD), the most common cause of dementia among the elderly, is a progressive neurodegenerative disease that affects 5.3 million people in the United States (Alzheimer’s’s, 2015). Ab clearance by enzyme-mediated transport and degrading contributes to the dynamic balance of Ab in the brain (Miners et al, 2011)
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