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  • PMID: 30596948 was deleted because it is a duplicate of PMID: 30596903
Brain. 2019 Jan 1;142(1):176-192. doi: 10.1093/brain/awy305.

MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation.

Author information

1
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China.
2
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
3
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY, USA.
4
Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, 136 ZhongshanEr Lu, Yuzhong District, Chongqing, China.
5
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
6
Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

MMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer's disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (β-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5' untranslated region (5'UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5'UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer's disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-β precursor protein processing, amyloid-β load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer's disease, via the translational regulation of BACE1.

PMID:
30596903
DOI:
10.1093/brain/awy305

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