Affiliations: [a] Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| [b] The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China
| [c] Nanjing, Jiangsu Key Laboratory for Molecular Medicine, Nanjing, China
| [d] Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, China
Correspondence:
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Correspondence to: Yun Xu, MD, PhD and Xiaolei Zhu, MD, PhD, Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu 210008, P.R. China. Tel.: +86 25 68182212; Fax: +86 25 83105208; E-mails: [email protected] (Yun Xu) and [email protected] (Xiaolei Zhu).
Abstract: Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment.
