Cattle Encephalon Glycoside and Ignotin Ameliorate Palmitoylation of PSD-95 and Enhance Expression of Synaptic Proteins in the Frontal Cortex of a APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Zhang, Yinghan^{a; b; 1} | Hu, Yazhuo^{a; 1} | Han, Zhitao^a | Geng, Yan^c | Xia, Zheng^d | Zhou, Yongsheng^b | Wang, Zhenfu^e | Wang, Yuanyuan^e | Kong, Eryan^f | Wang, Xiaoning^a | Jia, Jianjun^{a; *} | Zhang, Honghong^{a; *}

Affiliations: [a] Institute of Geriatrics, The 2nd Medical Center, Beijing Key Laboratory of Aging and Geriatrics, China National Clinical Research Center for Geriatric Disease, Chinese People’s Liberation Army General Hospital, Beijing, China | [b] Department of Neurology, Xuchang Hospital, Xuchang, Henan, China | [c] Department of Neurology, The 3rd Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China | [d] Department of Zhantansi, Medical District of Central Beijing, Chinese People’s Liberation Army General Hospital, Beijing, China | [e] Department of Neurology, The 2nd Medical Center, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Disease, Chinese People’s Liberation Army General Hospital, Beijing, China | [f] Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, Henan, China

Correspondence: [*] Correspondence to: Jianjun Jia and Honghong Zhang, Institute of Geriatrics, The 2nd Medical Center, Beijing Key Laboratory of Aging and Geriatrics, China National Clinical Research Center for Geriatric Disease, Chinese People’s Liberation Army General Hospital, Beijing, China. E-mail: [email protected] and [email protected].

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

Abstract: Background:Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer’s disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-β (Aβ) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aβ deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. Objective:In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 (PSD-95) palmitoylation, Aβ pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. Methods:Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. Results:CEGI treatment in APP/PS1 mice significantly reduced Aβ deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aβ expression and PSD-95 palmitoylation in APP/PS1 mice. Conclusion:Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment.

Keywords: Alzheimer’s disease, APP/PS1 transgenic mice, palmitoylation, postsynaptic density protein 95

DOI: 10.3233/JAD-220009

Journal: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 141-154, 2022