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.
Department of Neurology, Xuchang Hospital, Xuchang, Henan, China.
J Alzheimers Dis. 2022;88(1):141-154. doi: 10.3233/JAD-220009.
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.
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.
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.
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.
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.
突触蛋白中的突触异常是阿尔茨海默病（AD）的最初标志。AD 中突触蛋白的棕榈酰化水平较高与淀粉样β（Aβ）密切相关。牛脑苷脂和 ignotin（CEGI）已被证明在 APPswe/PS1dE9（APP/PS1）转基因 AD 小鼠中作为多靶点神经保护剂发挥作用。然而，目前尚不清楚 CEGI 是否可以影响 Aβ沉积，或者它是否通过调节蛋白棕榈酰化和转基因 AD 小鼠中突触蛋白的表达来实现这一点。
在本研究中，我们研究了 CEGI 调节突触后密度蛋白 95（PSD-95）棕榈酰化、Aβ病理和 APP/PS1 小鼠中突触相关蛋白表达的作用。
用 6.6 mL/kg 的 CEGI 对 5 月龄的 APP/PS1 小鼠进行腹腔内治疗 6 周。在治疗期末，APP/PS1 小鼠进行 Morris 水迷宫测试以测试其认知功能。用酰基辅酶 A 生物素交换（ABE）检测 PSD-95 棕榈酰化，免疫荧光染色检测 PSD-95、N-甲基-D-天冬氨酸受体亚基 2B（NR2B）和突触结合蛋白 1（SYT1）的表达。
CEGI 治疗 APP/PS1 小鼠可显著减少 Aβ沉积，缓解记忆缺陷，并降低前额叶皮质中的 PSD-95 棕榈酰化，同时显著增加 PSD-95、NR2B 和 SYT1 的表达。APP/PS1 小鼠中 Aβ 表达与 PSD-95 棕榈酰化之间存在显著相关性。
我们的研究结果表明，CEGI 改善了 AD 样神经病理学，可能通过抑制 PSD-95 棕榈酰化、改善学习记忆和增强突触相关蛋白的表达来实现，这代表了 AD 治疗的一种潜在疗法。
