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Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease | |
2010 | |
发表期刊 | JOURNAL OF BIOLOGICAL CHEMISTRY |
ISSN | 0021-9258 |
EISSN | 1083-351X |
卷号 | 285期号:36页码:27737-27744 |
发表状态 | 已发表 |
DOI | 10.1074/jbc.M110.117960 |
摘要 | Abnormal activation of calpain is implicated in synaptic dysfunction and participates in neuronal death in Alzheimer disease (AD) and other neurological disorders. Pharmacological inhibition of calpain has been shown to improve memory and synaptic transmission in the mouse model of AD. However, the role and mechanism of calpain in AD progression remain elusive. Here we demonstrate a role of calpain in the neuropathology in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, an established mouse model of AD. We found that overexpression of endogenous calpain inhibitor calpastatin (CAST) under the control of the calcium/calmodulindependent protein kinase II promoter in APP/PS1 mice caused a remarkable decrease of amyloid plaque burdens and prevented Tau phosphorylation and the loss of synapses. Furthermore, CAST overexpression prevented the decrease in the phosphorylation of the memory-related molecules CREB and ERK in the brain of APP/PS1 mice and improved spatial learning and memory. Interestingly, treatment of cultured primary neurons with amyloid-beta (A beta) peptides caused an increase in the level of beta-site APP-cleaving enzyme 1 (BACE1), the key enzyme responsible for APP processing and A beta production. This effect was inhibited by CAST overexpression. Consistently, overexpression of calpain in heterologous APP expressing cells up-regulated the level of BACE1 and increased A beta production. Finally, CAST transgene prevented the increase of BACE1 in APP/PS1 mice. Thus, calpain activation plays an important role in APP processing and plaque formation, probably by regulating the expression of BACE1. |
URL | 查看原文 |
收录类别 | SCI |
WOS研究方向 | Biochemistry & Molecular Biology |
WOS类目 | Biochemistry & Molecular Biology |
WOS记录号 | WOS:000281404100029 |
WOS关键词 | BETA-SECRETASE ACTIVITY ; IN-VIVO ; BRAIN-INJURY ; WATER-MAZE ; MICE ; PRESENILIN-1 ; NEURODEGENERATION ; DEPOSITION ; CALCIUM ; P25 |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/120339 |
专题 | 个人在本单位外知识产出 |
通讯作者 | Luo, Zhen-Ge |
作者单位 | 1.Chinese Acad Sci, Inst Neurosci, Shanghai 200031, Peoples R China 2.Chinese Acad Sci, State Key Lab Neurosci, Shanghai 200031, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China |
推荐引用方式 GB/T 7714 | Liang, Bin,Duan, Bao-Yu,Zhou, Xiu-Ping,et al. Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2010,285(36):27737-27744. |
APA | Liang, Bin,Duan, Bao-Yu,Zhou, Xiu-Ping,Gong, Jia-Xin,&Luo, Zhen-Ge.(2010).Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease.JOURNAL OF BIOLOGICAL CHEMISTRY,285(36),27737-27744. |
MLA | Liang, Bin,et al."Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease".JOURNAL OF BIOLOGICAL CHEMISTRY 285.36(2010):27737-27744. |
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