Research Article: HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer’s disease

Date Published: August 03, 2017

Publisher: John Wiley and Sons Inc.

Author(s): Xiaolei Zhu, Sulei Wang, Linjie Yu, Jiali Jin, Xing Ye, Yi Liu, Yun Xu.

http://doi.org/10.1111/acel.12642

Abstract

The 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.

Partial Text

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). Although the precise mechanisms of AD are largely unknown, the deposition of beta‐amyloid (Aβ) is a key neuropathological hallmark. AD is closely associated with synaptic dysfunction, glial reactivity, and neuronal loss (Selkoe & Hardy, 2016). Aβ is derived from the proteolytic metabolism of transmembrane β‐amyloid precursor protein (APP). In the amyloidogenic pathway, Aβ is produced by sequential cleavage of APP by β‐secretase and γ‐secretase; in the nonamyloidogenic pathway, APP is consecutively cleaved by α‐secretase and γ‐secretase, which yields smaller Aβ fragments and neuroprotective sAPPα (Selkoe, 2013). In addition, Aβ clearance by enzyme‐mediated transport and degrading contributes to the dynamic balance of Aβ in the brain (Miners et al., 2011).

In the current study, we investigate the possible effect of HDAC3 on spatial memory deficits and the pathogenesis of AD, and our data have shown that (i) nuclear HDAC3 is significantly increased in the hippocampus of 6‐ and 9‐month‐old APP/PS1 mice compared with that in age‐matched wild‐type C57BL/6 (B6) mice; (ii) lentivirus‐mediated inhibition of HDAC3 in the hippocampus attenuates spatial memory deficits, decreases amyloid plaque load and Aβ levels, alleviates microglial activation, and increases dendritic spine density in 9‐month‐old APP/PS1 mice; and (iii) lentivirus‐mediated overexpression of HDAC3 in the hippocampus increases Aβ levels, activates microglia, and decreases dendritic spine density in 6‐month‐old APP/PS1 mice. Furthermore, inhibition or overexpression of HDAC3 does not alter the levels of phosphorylated tau in the hippocampus of 6‐ and 9‐month‐old APP/PS1 mice (Fig. S7, Supporting information).

This work was supported by the National Natural Science Foundation of China (81200839 and 81671055 to XLZ, 81300988 to JLJ, and 81230026, 81630028, and 81171085 to YX), and Jiangsu Provinical Key Medical Discipline (ZDXKA2016020 to YX).

YX conceived and designed the research; XLZ, SLW, LJY, and JLJ carried out experiments; XY and YL analyzed the data; and XLZ, SLW, and YX wrote the manuscript.

The authors declare no conflict of interest.

 

Source:

http://doi.org/10.1111/acel.12642

 

Leave a Reply

Your email address will not be published.