神经药理学报

神经药理学报 ›› 2018, Vol. 8 ›› Issue (4): 52-53.

• Session 3A: Cognition in Alzheimer’s Disease: Animal Models and Intracellular Mechanisms • 上一篇    下一篇

The Effect of PHA-543613 on Memory Disorders in Presenilin1 and Presenilin2 Conditional Double Knockout Mice

WANG Jia-Yue，DUAN Yan-Hong，Wang Xin-He，Zhang Xu-Liang，Xu Mei-Chen, Cao Xiao-Hua *   

  1. Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, China
  • 出版日期:2018-08-26 发布日期:2018-11-16
  • 基金资助:

    This research was supported by grants from National Natural Science Fund of China (31471077) and MOST China-Israel cooperation(2016YFE0130500

The Effect of PHA-543613 on Memory Disorders in Presenilin1 and Presenilin2 Conditional Double Knockout Mice

WANG Jia-Yue，DUAN Yan-Hong，Wang Xin-He，Zhang Xu-Liang，Xu Mei-Chen, Cao Xiao-Hua *   

  1. Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, China
  • Online:2018-08-26 Published:2018-11-16
  • Supported by:

    This research was supported by grants from National Natural Science Fund of China (31471077) and MOST China-Israel cooperation(2016YFE0130500

摘要： The mutation in the amyloid-beta precursor protein (APP) and presenilin genes (PSEN1 and PSEN2) cause autosomal dominant Alzheimer’s diease (ADAD) which is typically associated with early-onset familial Alzheimer’s disease (FAD), however, the mechanism by which presenilin mutations cause memory disorders and neurodegeneration remains poorly understood. In the present study, using Presenilin-1 and Presenilin-2 double knockout mice (cDKO mice), we observed that the impaired spatial reference memory, spatial working memory and contextual fear memory in cDKO mice. Consistently, deficits of basal synaptic transmission and LTP formation, as well as down-regulation of PI3K/Akt signaling pathway at hippocampus in cDKO mice. Furthermore, we found the expression levels of α7-nicotinic ACh receptors (α7nAChRs), NMDAR and AMPAR composition subunits, which related to synaptic plasticity and memory, were decreased at hippocampus in cDKO mice. Importantly, all above deficits could be reversed by α7nAChR agonist PHA-543613. Taken together, our results indicate that knockout of PS1 and PS2 can disrupt the function of α7nAChR, thereby down-regulate activation of PI3K/Akt signaling pathway, reduce the synaptic expression levels of NMDAR and AMPAR composition subunits at hippocampus, consequently cause neuronal apoptosis, disrupt basal synaptic transmission and LTP formation at hippocampus, finally impair hippocampal-dependent memory.

关键词: Alzheimer&rsquo, s disease, presenilin, neuronal apoptosis, synaptic plasticity, memory

Abstract: The mutation in the amyloid-beta precursor protein (APP) and presenilin genes (PSEN1 and PSEN2) cause autosomal dominant Alzheimer’s diease (ADAD) which is typically associated with early-onset familial Alzheimer’s disease (FAD), however, the mechanism by which presenilin mutations cause memory disorders and neurodegeneration remains poorly understood. In the present study, using Presenilin-1 and Presenilin-2 double knockout mice (cDKO mice), we observed that the impaired spatial reference memory, spatial working memory and contextual fear memory in cDKO mice. Consistently, deficits of basal synaptic transmission and LTP formation, as well as down-regulation of PI3K/Akt signaling pathway at hippocampus in cDKO mice. Furthermore, we found the expression levels of α7-nicotinic ACh receptors (α7nAChRs), NMDAR and AMPAR composition subunits, which related to synaptic plasticity and memory, were decreased at hippocampus in cDKO mice. Importantly, all above deficits could be reversed by α7nAChR agonist PHA-543613. Taken together, our results indicate that knockout of PS1 and PS2 can disrupt the function of α7nAChR, thereby down-regulate activation of PI3K/Akt signaling pathway, reduce the synaptic expression levels of NMDAR and AMPAR composition subunits at hippocampus, consequently cause neuronal apoptosis, disrupt basal synaptic transmission and LTP formation at hippocampus, finally impair hippocampal-dependent memory.

Key words: Alzheimer&rsquo, s disease, presenilin, neuronal apoptosis, synaptic plasticity, memory