Department of Biophysics, Faculty of Medicine, Akdeniz University, Arapsuyu, 07070, Antalya, Turkey.
Department of Medical Imaging Techniques, Vocational School of Health Services, Akdeniz University, Arapsuyu, 07070, Antalya, Turkey.
Mol Neurobiol. 2023 Jul;60(7):4030-4048. doi: 10.1007/s12035-023-03334-7. Epub 2023 Apr 5.
Cyclo (his-pro-CHP) plus zinc (Zn) (Cyclo-Z) is the only known chemical that increases the production of insulin-degrading enzyme (IDE) and decreases the number of inactive insulin fragments in cells. The aim of the present study was to systematically characterize the effects of Cyclo-Z on the insulin pathway, memory functions, and brain oscillations in the Alzheimer's disease (AD) rat model. The rat model of AD was established by bilateral injection of Aβ42 oligomer (2,5nmol/10μl) into the lateral ventricles. Cyclo-Z (10mg Zn+2/kg and 0.2mg CHP/kg) gavage treatment started seven days after Aβ injection and lasted for 21 days. At the end of the experimental period, memory tests and electrophysiological recordings were performed, which were followed by the biochemical analysis. Aβ42 oligomers led to a significant increase in fasting blood glucose, serum insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and phospho-tau-Ser356 levels. Moreover, Aβ42 oligomers caused a significant decrement in body weight, hippocampal insulin, brain insulin receptor substrate (IRS-Ser612), and glycogen synthase kinase-3 beta (GSK-3β) levels. Also, Aβ42 oligomers resulted in a significant reduction in memory. The Cyclo-Z treatment prevented the observed alterations in the ADZ group except for phospho-tau levels and attenuated the increased Aβ42 oligomer levels in the ADZ group. We also found that the Aβ42 oligomer decreased the left temporal spindle and delta power during ketamine anesthesia. Cyclo-Z treatment reversed the Aβ42 oligomer-related alterations in the left temporal spindle power. Cyclo-Z prevents Aβ oligomer-induced changes in the insulin pathway and amyloid toxicity, and may contribute to the improvement of memory deficits and neural network dynamics in this rat model.
环（组-脯-CHP）加锌（Zn）（环-Z）是唯一已知能增加胰岛素降解酶（IDE）产量并减少细胞内无活性胰岛素片段数量的化学物质。本研究的目的是系统地研究环-Z 对阿尔茨海默病（AD）大鼠模型胰岛素途径、记忆功能和脑振荡的影响。AD 大鼠模型通过双侧脑室注射 Aβ42 寡聚体（2.5nmol/10μl）建立。环-Z（10mg Zn+2/kg 和 0.2mg CHP/kg）灌胃治疗在 Aβ 注射后 7 天开始，持续 21 天。在实验期末，进行记忆测试和电生理记录，随后进行生化分析。Aβ42 寡聚体导致空腹血糖、血清胰岛素、胰岛素稳态模型评估（HOMA-IR）和磷酸化 tau-Ser356 水平显著升高。此外，Aβ42 寡聚体导致体重、海马胰岛素、脑胰岛素受体底物（IRS-Ser612）和糖原合酶激酶-3β（GSK-3β）水平显著降低。此外，Aβ42 寡聚体导致记忆显著下降。环-Z 治疗可预防 ADZ 组观察到的变化，除了磷酸化 tau 水平外，还可减轻 ADZ 组中 Aβ42 寡聚体水平的增加。我们还发现，Aβ42 寡聚体在氯胺酮麻醉期间降低了左侧颞部纺锤波和 delta 功率。环-Z 治疗逆转了 Aβ42 寡聚体相关的左侧颞部纺锤波功率改变。环-Z 可预防 Aβ 寡聚体诱导的胰岛素途径和淀粉样毒性变化，并可能有助于改善该大鼠模型的记忆缺陷和神经网络动力学。
