Muscone Ameliorates Synaptic Dysfunction and Cognitive Deficits in APP/PS1 Mice

Article type: Research Article

Authors: Liu, Yi^{a; b; 1} | Bian, Huijie^{a; b; c; 1} | Xu, Siyi^{a; b; d} | Shu, Shu^{a; b} | Jia, Junqiu^{a; b} | Chen, Jian^{a; b} | Cao, Xiang^{a; b} | Bao, Xinyu^{a; b} | Gu, Yue^{a; b} | Xia, Shengnan^{a; b} | Yang, Hui^e | Yu, Linjie^{a; b} | Xu, Yun^{a; b; c; d; *} | Zhu, Xiaolei^{a; b; *}

Affiliations: [a] Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China | [b] Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China | [c] Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China | [d] Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, China | [e] Department of Neurology, Nanjing Hospital of Chinese Medicine Affilicated to Nanjing University of Chinese Medicine, Nanjing, China

Correspondence: [*] Correspondence to: Correspondingauthor [*]Yun Xu, MD, PhD or 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-mail: [email protected] (Yun Xu) or E-mail: [email protected] (Xiaolei Zhu).

Note: [1] These authors contributed equally to this study.

Abstract: Background:Dysfunction of synaptic plasticity leads to memory impairment in Alzheimer’s disease (AD). Muscone (Mus) has shown neuroprotective effects in cerebral ischemic models. However, little is known of Mus effects on AD. Objective:To investigate the effects of Mus on memory functions and synaptic plasticity in 6-month-old APP/PS1 double-transgenic mice and explore the potential mechanisms. Methods:Mus was intraperitoneally injected into APP/PS1 or wild-type mice, and cognitive function was assessed by Novel object recognition and Morris water maze tests. The levels of amyloid-β (Aβ) were evaluated by immunofluorescence staining and ELISA. Synaptic morphology and plasticity were evaluated by Golgi staining and long-term potentiation. Cell viability was examined by Cell Counting Kit-8 assay. The protein levels of histone deacetylase 2 (HDAC2) were accessed by western blotting and Immunofluorescence staining. The protein levels of microtubule associated protein 2 and synaptophysin were analyzed by immunofluorescence staining. The ubiquitination of HDAC2 was examined by co-immunoprecipitation. The interaction of Mus with HDAC2 was predicted by molecular docking analysis. Results:Mus treatment attenuated memory dysfunction, reduced Aβ level, and enhanced synaptic plasticity in APP/PS1 mice. In addition, Mus treatment decreased the level of HDAC2 in the hippocampus of APP/PS1 mice and Aβ1–42-induced primary neurons, which might be associated with increased HDAC2 ubiquitination induced by HDAC2 and Mus interaction. Conclusion:Mus protected against synaptic plasticity and memory impairment in APP/PS1 mice, and enhanced HDAC2 degradation via ubiquitination, indicating that Mus was a potential drug for AD treatment.

Keywords: Alzheimer’s disease, amyloid-β, HDAC2, muscone, synaptic plasticity

DOI: 10.3233/JAD-200188

Journal: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 491-504, 2020