Yu Linjie, Liu Yi, Jin Yuexinzi, Cao Xiang, Chen Jian, Jin Jiali, Gu Yue, Bao Xinyu, Ren Zhuoying, Xu Yun, Zhu Xiaolei
Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
J Alzheimers Dis. 2018;61(4):1411-1424. doi: 10.3233/JAD-170844.
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.
淀粉样蛋白-β（Aβ）会引发一阵氧化应激，并在阿尔茨海默病（AD）的发病机制中起关键作用。我们之前的研究结果表明，抑制组蛋白去乙酰化酶3（HDAC3）可改善9月龄APPswe/PS1dE9（APP/PS1）小鼠的空间记忆缺陷，并减轻其大脑中的Aβ负担。在本研究中，我们调查了HDAC3抑制在AD体内和体外模型氧化应激中的作用。HDAC3主要在神经元中被检测到，抑制HDAC3可显著减少活性氧的产生，并提高原代皮质神经元的活力。此外，抑制HDAC3可减轻6月龄APP/PS1小鼠的空间记忆功能障碍，并如TUNEL染色所示降低海马体中的凋亡率。抑制HDAC3还可减少APP/PS1小鼠海马体中脂质过氧化、蛋白质氧化和DNA/RNA氧化的标志物。此外，抑制HDAC3可使APP/PS1小鼠海马体中的c-Abl/MST1/YAP信号通路失活。总之，我们的数据表明，抑制HDAC3可减轻APP/PS1小鼠的空间记忆缺陷并抑制氧化应激；这些结果表明了一种潜在的AD治疗策略。
