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

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

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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.
Department of Traditional Chinese Medicine, Wuhan Red Cross Hospital, Wuhan, China.
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.


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.


Alzheimer's disease; cAMP response element binding protein; endoplasmic reticulum; glycogen synthase kinase-3; spatial memory deficits

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