Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China; Institute of Neurobiology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
Neurobiol Learn Mem. 2020 Feb;168:107154. doi: 10.1016/j.nlm.2019.107154. Epub 2020 Jan 2.
Cognitive impairment in Alzheimer's disease (AD) is characterized by being deficient at learning and memory. Aβ oligomers have been shown to impair rodent cognitive function. We previously demonstrated that activation of α7nAChR, inhibition of p38 or JNK could alleviate Aβ-induced memory deficits in Y maze test. In this study, we investigated whether the effects of α7nAChR and MAPKs on Y maze test is reproducible with a hippocampus-dependent spatial memory test such as Morris water maze. We also assessed the possible co-existence of hippocampus-independent recognition memory dysfunction using a novel object recognition test and an alternative and stress free hippocampus-dependent recognition memory test such as the novel place recognition. Besides, previous research from our lab has shown that MAPKs pathways regulate Aβ internalization through mediating α7nAChR. In our study, whether MAPKs pathways exert their functions in cognition by modulating α7nAChR through regulating glutamate receptors and synaptic protein, remain little known. Our results showed that activation of α7nAChR restored spatial memory, novel place recognition memory, and short-term and long-term memory in novel object recognition. Inhibition of p38 restored spatial memory and short-term and long-term memory in novel object recognition. Inhibition of ERK restored short-term memory in novel object recognition and novel place recognition memory. Inhibition of JNK restored spatial memory, short-term memory in novel object recognition and novel place recognition memory. Beside this, the activation of α7nAChR, inhibition of p38 or JNK restored Aβ-induced levels of NMDAR1, NMDAR2A, NMDAR2B, GluR1, GluR2 and PSD95 in Aβ-injected mice without influencing synapsin 1. In addition, these treatments also recovered the expression of acetylcholinesterase (AChE). Finally, we found that the inhibition of p38 or JNK resulted in the upregulation of α7nAChR mRNA levels in the hippocampus. Our results indicated that inhibition of p38 or JNK MAPKs could alleviate Aβ-induced spatial memory deficits through regulating activation of α7nAChR via recovering memory-related proteins. Moreover, p38, ERK and JNK MAPKs exert different functions in spatial and recognition memory.
阿尔茨海默病（AD）的认知障碍表现为学习和记忆能力缺陷。Aβ寡聚体已被证明会损害啮齿动物的认知功能。我们之前的研究表明，激活α7nAChR、抑制 p38 或 JNK 可以减轻 Y 迷宫测试中 Aβ引起的记忆缺陷。在这项研究中，我们研究了α7nAChR 和 MAPKs 是否可以通过海马依赖性空间记忆测试（如 Morris 水迷宫）来重现对 Y 迷宫测试的影响。我们还使用新物体识别测试和替代且无压力的海马依赖性识别记忆测试（如新位置识别）评估了海马不依赖的识别记忆功能障碍的可能共存。此外，我们实验室的先前研究表明，MAPKs 途径通过调节α7nAChR 来调节 Aβ内化。在我们的研究中，MAPKs 途径是否通过调节谷氨酸受体和突触蛋白来调节α7nAChR 发挥其认知功能仍知之甚少。我们的研究结果表明，激活α7nAChR 恢复了空间记忆、新位置识别记忆、新物体识别的短期和长期记忆。抑制 p38 恢复了新物体识别的空间记忆、短期和长期记忆。抑制 ERK 恢复了新物体识别和新位置识别记忆的短期记忆。抑制 JNK 恢复了空间记忆、新物体识别和新位置识别记忆的短期记忆。除此之外，激活α7nAChR、抑制 p38 或 JNK 恢复了 Aβ 诱导的 NMDAR1、NMDAR2A、NMDAR2B、GluR1、GluR2 和 PSD95 水平在 Aβ 注射小鼠中，而不影响突触素 1。此外，这些治疗方法还恢复了乙酰胆碱酯酶 (AChE) 的表达。最后，我们发现抑制 p38 或 JNK 导致海马中α7nAChR mRNA 水平上调。我们的研究结果表明，抑制 p38 或 JNK MAPKs 可以通过恢复记忆相关蛋白来调节α7nAChR 的激活，从而减轻 Aβ 引起的空间记忆缺陷。此外，p38、ERK 和 JNK MAPKs 在空间和识别记忆中发挥不同的作用。
