Hypoxia-triggered m-calpain activation evokes endoplasmic reticulum stress and neuropathogenesis in a transgenic mouse model of Alzheimer's disease

Autor:	Tao Wang, Chun-Yan Wang, Li An, Bao-Lu Zhao, Ye Xu, Xu Wang, Zhan-You Wang, Jian-Hui Cai, Jing-Wei Xie
Rok vydání:	2013
Předmět:	Genetically modified mouse medicine.medical_specialty Mice Transgenic Biology Endoplasmic Reticulum Hippocampus Amyloid beta-Protein Precursor Mice Random Allocation Downregulation and upregulation GSK-3 Alzheimer Disease Physiology (medical) Internal medicine Cell Line Tumor medicine Presenilin-1 Animals Humans Pharmacology (medical) Glycogen synthase Hypoxia Maze Learning Pharmacology Calpain Endoplasmic reticulum Original Articles Endoplasmic Reticulum Stress Cell biology Mice Inbred C57BL Psychiatry and Mental health Disease Models Animal Endocrinology Apoptosis biology.protein Unfolded protein response Female
Zdroj:	CNS neurosciencetherapeutics. 19(10)
ISSN:	1755-5949
Popis:	Summary Background Previous studies have demonstrated that endoplasmic reticulum (ER) stress is activated in Alzheimer's disease (AD) brains. ER stress–triggered unfolded protein response (UPR) leads to tau phosphorylation and neuronal death. Aims In this study, we tested the hypothesis that hypoxia-induced m-calpain activation is involved in ER stress-mediated AD pathogenesis. Method We employed a hypoxic exposure in APP/PS1 transgenic mice and SH-SY5Y cells overexpressing human Swedish mutation APP (APPswe). Results We observed that hypoxia impaired spatial learning and memory in the APP/PS1 mouse. In the transgenic mouse brain, hypoxia increased the UPR, upregulated apoptotic signaling, enhanced the activation of calpain and glycogen synthase kinase-3β (GSK3β), and increased tau hyperphosphorylation and β-amyloid deposition. In APPswe cells, m-calpain silencing reduced hypoxia-induced cellular dysfunction and resulted in suppression of GSK3β activation, ER stress and tau hyperphosphorylation reduction as well as caspase pathway suppression. Conclusion These findings demonstrate that hypoxia-induced abnormal calpain activation may increase ER stress-induced apoptosis in AD pathogenesis. In contrast, a reduction in the expression of the m-calpain isoform reduces ER stress-linked apoptosis that is triggered by hypoxia. These findings suggest that hypoxia-triggered m-calpain activation is involved in ER stress-mediated AD pathogenesis. m-calpain is a potential target for AD therapeutics.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::367474cc6469a3e4d923c159c1e92f09 https://pubmed.ncbi.nlm.nih.gov/23889979 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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