Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China.
Psychopharmacology (Berl). 2018 Jan;235(1):337-349. doi: 10.1007/s00213-017-4775-6. Epub 2017 Nov 9.
Alzheimer's disease (AD) is characterized by memory loss and synaptic damage. Previous studies suggested that xanthoceraside decreases glutamate-induced PC12 cell death, ameliorates memory deficits, and increases the number of dendritic spines in AD mice. These results indicated that xanthoceraside might have activities that protect synaptic plasticity. Herein, we detected the effect of xanthoceraside on synaptic function.
Three-month-old APP/PS1 transgenic mice were orally treated with xanthoceraside (0.02, 0.08, or 0.32 mg/kg) once daily for 4 months and then behavioral tests were performed. LTP and Fluo-4/AM were carried out in vivo and in vitro, respectively. CaMKII-GluR1 and NR2B-associated proteins on synapses were measured.
Xanthoceraside administration alleviated learning-memory deficits and increased the LTP in APP/PS1 transgenic mice. Meanwhile, xanthoceraside increased the expression of pT286-CaMKII in synaptic and extrasynaptic pools and CaMKII, pS831-GluR1, and GluR1 in synaptic pools. In addition, xanthoceraside increased the total pY1472-NR2B and NR2B expression and increased the levels of pY1472-NR2B in synaptic and extrasynaptic pools and NR2B in synaptic pools. However, NR2B was decreased in extrasynaptic pools, which might be associated with decreased expression of STEP and pY531-Fyn. In vitro studies showed that xanthoceraside inhibited intracellular calcium overload and increased the number of and extended the length of dendrites in primary hippocampal neurons compared with the Aβ group.
The mechanism of xanthoceraside on ameliorating learning-memory deficits might be related to decrease intracellular calcium overload, increase CaMKII-GluR1 proteins, and up-regulate trafficking of pY1472-NR2B at synapse, thereby improving LTP in APP/PS1 transgenic mice.
阿尔茨海默病（AD）的特征是记忆丧失和突触损伤。先前的研究表明，梓醇可降低谷氨酸诱导的 PC12 细胞死亡，改善记忆缺陷，并增加 AD 小鼠的树突棘数量。这些结果表明梓醇可能具有保护突触可塑性的活性。在此，我们检测了梓醇对突触功能的影响。
3 月龄 APP/PS1 转基因小鼠每日口服梓醇（0.02、0.08 或 0.32mg/kg），连续 4 个月，然后进行行为学测试。分别在体和离体进行 LTP 和 Fluo-4/AM 实验，测量突触上的 CaMKII-GluR1 和 NR2B 相关蛋白。
梓醇给药可改善 APP/PS1 转基因小鼠的学习记忆缺陷并增加 LTP。同时，梓醇增加了突触和突触外池 pT286-CaMKII 和突触池 CaMKII、pS831-GluR1 和 GluR1 的表达。此外，梓醇增加了总 pY1472-NR2B 和 NR2B 的表达，并增加了突触和突触外池 pY1472-NR2B 和突触池 NR2B 的水平。然而，NR2B 在突触外池减少，这可能与 STEP 和 pY531-Fyn 的表达减少有关。体外研究表明，与 Aβ 组相比，梓醇可抑制原代海马神经元内钙超载，增加树突数量并延长其长度。
梓醇改善学习记忆缺陷的机制可能与减少细胞内钙超载、增加 CaMKII-GluR1 蛋白和上调突触 pY1472-NR2B 转运有关，从而改善 APP/PS1 转基因小鼠的 LTP。
