Alzheimer’s disease (AD) is behaviorally characterized by memory impairments, and pathologically by amyloid β1–42 (Aβ1–42) plaques and tangles. Aβ binds to excitatory synapses and disrupts their transmission due to dysregulation of the glutamate receptors. Here we hypothesized that chronic inhibition of the endocytosis of AMPA receptors together with GluN2B subunit of NMDA receptors might improve cognition deficit induced by Aβ(1–42) neurotoxicity. Forty male Wistar rats were used in this study and divided into 5 groups: Saline + Saline, Aβ+Saline, Aβ+Ifen (Ifenprodil, 3 nmol /2 weeks), Aβ+GluR23Y (Tat-GluR23Y 3 μmol/kg/2 weeks) and Aβ+Ifen+GluR23Y (same doses and durations). Aβ(1–42) neurotoxicity was induced by intracerebroventricular (ICV) injection of Aβ1–42 (2 μg/μl/side), and then animals received the related treatments for 14 days. Cognitive performance of rats and hippocampal level of cAMP-response element-binding (CREB) were evaluated using Morris Water Maze (MWM), and western blotting respectively. Obtained data from the acquisition trials were analyzed by two way Anova and Student T test. Also one way Analysis of variance (ANOVA) with post hoc Tuckey were used to clarify between groups differences in probe test. The Group receiving Aβ, showed significant cognition deficit (long latency to platform and short total time spent in target quadrant (TTS), parallel with lower level of hippocampal CREB, versus vehicle group. While, Aβ+ GluR23Y exhibited the shortest latency to platform and the longest TTS during the probe test, parallel with the higher hippocampal level of CREB compared with other groups. The present study provides evidence that chronic administration of Tat-GluR23Y; an inhibitor of GluA2-AMPARs endocytosis, successfully restores spatial memory impaired by amyloid beta neurotoxicity targeting CREB signaling pathway.

阿尔茨海默病 (AD) 的行为特征是记忆障碍，病理特征是淀粉样蛋白 β1-42 (Aβ1-42) 斑块和缠结。 Aβ 与兴奋性突触结合，并由于谷氨酸受体失调而破坏其传递。在此，我们假设长期抑制 AMPA 受体与 NMDA 受体 GluN2B 亚基的内吞作用可能会改善 Aβ(1-42) 神经毒性引起的认知缺陷。本研究使用 40 只雄性 Wistar 大鼠，分为 5 组：Saline + Saline、Aβ+Saline、Aβ+Ifen（Ifenprodil，3 nmol/2 周）、Aβ+GluR23Y（Tat-GluR23Y 3 μmol/kg/2 周） ) 和 Aβ+Ifen+GluR23Y（相同剂量和持续时间）。通过脑室内（ICV）注射Aβ1-42（2μg/μl/侧）诱导Aβ（1-42）神经毒性，然后动物接受相关治疗14天。分别使用莫里斯水迷宫 (MWM) 和蛋白质印迹法评估大鼠的认知表现和海马 cAMP 反应元件结合 (CREB) 水平。通过双向方差分析和学生 T 检验分析从采集试验中获得的数据。还使用事后 Tuckey 进行方差分析 (ANOVA) 的一种方式来澄清探针测试中组间的差异。与媒介物组相比，接受 Aβ 的组表现出显着的认知缺陷（平台潜伏期长，目标象限 (TTS) 花费的总时间短，同时海马 CREB ​​水平较低。而 Aβ+ GluR23Y 表现出平台潜伏期最短，并且在目标象限 (TTS) 上花费的总时间短。探针测试期间 TTS 最长，与其他组相比，CREB ​​的海马水平较高。 本研究提供了长期服用 Tat-GluR23Y 的证据； GluA2-AMPAR 内吞作用的抑制剂，成功恢复因针对 CREB ​​信号通路的淀粉样蛋白神经毒性而受损的空间记忆。