Hypoxia‐Triggered m‐Calpain Activation Evokes Endoplasmic Reticulum Stress and Neuropathogenesis in a Transgenic Mouse Model of Alzheimer's Disease. (27th July 2013)

• Record Type: Journal Article
• Authors: Wang, Chun‐Yan; Xie, Jing‐Wei; Wang, Tao; Xu, Ye; Cai, Jian‐Hui; Wang, Xu; Zhao, Bao‐Lu; An, Li; Wang, Zhan‐You
• Is Part Of: CNS neuroscience & therapeutics. Volume 19:Number 10(2013)
• Page Start: 820
• Page End: 833
• Publication Date: 2013-07-27
• Subjects: Alzheimer's disease -- APP/PS1 transgenic mouse -- Calpain -- Endoplasmic reticulum stress -- Glycogen synthase kinase 3 -- Hypoxia -- RNA interference; Neuropharmacology -- Periodicals; Central nervous system -- Diseases -- Effect of drugs on -- Periodicals; 612.8
• DOI: 10.1111/cns.12151
• Languages: English
• ISSNs: 1755-5930

Abstract

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.