Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease
Liang, Bin; Duan, Bao-Yu; Zhou, Xiu-Ping; Gong, Jia-Xin; Luo, Zhen-Ge
2010
Source PublicationJOURNAL OF BIOLOGICAL CHEMISTRY
ISSN0021-9258
EISSN1083-351X
Volume285Issue:36Pages:27737-27744
Status已发表
DOI10.1074/jbc.M110.117960
Abstract

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.

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Indexed BySCI
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000281404100029
WOS KeywordBETA-SECRETASE ACTIVITY ; IN-VIVO ; BRAIN-INJURY ; WATER-MAZE ; MICE ; PRESENILIN-1 ; NEURODEGENERATION ; DEPOSITION ; CALCIUM ; P25
Original Document TypeArticle
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Cited Times:85[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/120339
Collection个人在本单位外知识产出
Corresponding AuthorLuo, Zhen-Ge
Affiliation1.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
Recommended Citation
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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