Premium
Endoplasmic reticulum stress induces spatial memory deficits by activating GSK‐3 in Alzheimer’s disease
Author(s) -
Wang XiaoMing
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041764
Subject(s) - creb , unfolded protein response , endoplasmic reticulum , synaptic plasticity , neuroscience , protein kinase a , endocrinology , medicine , hippocampus , phosphorylation , gsk 3 , synapse , chemistry , biology , microbiology and biotechnology , transcription factor , biochemistry , receptor , gene
Background Endoplasmic reticulum (ER) stress is involved in Alzheimer’s disease (AD), but the mechanism remains unclear. Method Tunicamycin (TM), a recognized ER stress inducer, was injected into the brain ventricle of Sprague‐Dawley (SD) rats to induce the unfolded protein response (UPR). Rats was divided into 3 groups for the brain lateral ventricle injections with DMSO, TM, or TM + SB, respectively. The behavioural test was conducted after 24 and 48 hours, respectively. Then the rats were sacrificed. Brain samples were collected for further protein analysis and specific stains. Result TM‐induced UPR was convinced by enhanced phosphorylation of pancreatic ER kinase (PERK), inositol‐requiring enzyme‐1 (IRE‐1), and transcription factor‐6 (ATF‐6) activation. Behavioural test demonstrated UPR induced spatialmemory deficits and impairments of synaptic plasticity in the rats. After TM treatment, GSK‐3β was activated. Phosphorylation of cAMP response element binding protein at Ser129 (pS129‐CREB) was up‐regulated 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, synaptic plasticity, and spatial memory impairment with restoration of pS129‐CREB. Conclusion TM‐induced UPR causes AD‐like spatial memory deficits and synapse impairments by activating GSK‐3b/pS129‐CREB pathway. GSK‐3 inhibition might be a promising therapy in AD treatment.