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内质网应激通过激活 GSK-3 诱导空间记忆缺陷。

Endoplasmic reticulum stress induces spatial memory deficits by activating GSK-3.

机构信息

Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cell Molecular Biology Laboratory of Basic Medical College, Hubei University of Chinese Medicine, Wuhan, China.

出版信息

J Cell Mol Med. 2018 Jul;22(7):3489-3502. doi: 10.1111/jcmm.13626. Epub 2018 Apr 19.

DOI:10.1111/jcmm.13626
PMID:29675957
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6010738/
Abstract

Endoplasmic reticulum (ER) stress is involved in Alzheimer's disease (AD), but the mechanism is not fully understood. Here, we injected tunicamycin (TM), a recognized ER stress inducer, into the brain ventricle of Sprague-Dawley (SD) rats to induce the unfolded protein response (UPR), demonstrated by the enhanced phosphorylation of pancreatic ER kinase (PERK), inositol-requiring enzyme-1 (IRE-1) and activating transcription factor-6 (ATF-6). We observed that UPR induced spatial memory deficits and impairments of synaptic plasticity in the rats. After TM treatment, GSK-3β was activated and phosphorylation of cAMP response element binding protein at Ser129 (pS129-CREB) was increased with an increased nuclear co-localization of pY126-GSK-3β and pS129-CREB. Simultaneous inhibition of GSK-3β by hippocampal infusion of SB216763 (SB) attenuated TM-induced UPR and spatial memory impairment with restoration of pS129-CREB and synaptic plasticity. We concluded that UPR induces AD-like spatial memory deficits with mechanisms involving GSK-3β/pS129-CREB pathway.

摘要

内质网（ER）应激参与阿尔茨海默病（AD），但其机制尚不完全清楚。在这里，我们向 Sprague-Dawley（SD）大鼠脑室内注射了衣霉素（TM），一种公认的 ER 应激诱导剂，以诱导未折叠蛋白反应（UPR），其表现为胰腺 ER 激酶（PERK）、肌醇需求酶-1（IRE-1）和激活转录因子-6（ATF-6）的磷酸化增强。我们观察到 UPR 诱导大鼠空间记忆缺陷和突触可塑性损伤。TM 处理后，GSK-3β被激活，pS129-CREB 的磷酸化增加，pY126-GSK-3β和 pS129-CREB 的核共定位增加。通过海马内输注 SB216763（SB）同时抑制 GSK-3β可减轻 TM 诱导的 UPR 和空间记忆障碍，并恢复 pS129-CREB 和突触可塑性。我们的结论是，UPR 诱导 AD 样空间记忆缺陷，其机制涉及 GSK-3β/pS129-CREB 途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/dd6350843659/JCMM-22-3489-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/9447920f3e18/JCMM-22-3489-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/7e6fa76eef38/JCMM-22-3489-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/8fe25f27fecc/JCMM-22-3489-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/9d9dd1aff4a9/JCMM-22-3489-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/00720d6afc15/JCMM-22-3489-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/dd6350843659/JCMM-22-3489-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/9447920f3e18/JCMM-22-3489-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/7e6fa76eef38/JCMM-22-3489-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/8fe25f27fecc/JCMM-22-3489-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/9d9dd1aff4a9/JCMM-22-3489-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/00720d6afc15/JCMM-22-3489-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ae1/6010738/dd6350843659/JCMM-22-3489-g006.jpg

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