PMID- 30596903 OWN - NLM STAT- MEDLINE DCOM- 20190820 LR - 20200615 IS - 1460-2156 (Electronic) IS - 0006-8950 (Print) IS - 0006-8950 (Linking) VI - 142 IP - 1 DP - 2019 Jan 1 TI - MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation. PG - 176-192 LID - 10.1093/brain/awy305 [doi] AB - 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 (beta-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-beta precursor protein processing, amyloid-beta 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. FAU - Zhu, Bing-Lin AU - Zhu BL AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China. FAU - Long, Yan AU - Long Y AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China. FAU - Luo, Wei AU - Luo W AD - Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. FAU - Yan, Zhen AU - Yan Z AD - Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY, USA. FAU - Lai, Yu-Jie AU - Lai YJ AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China. FAU - Zhao, Li-Ge AU - Zhao LG AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China. FAU - Zhou, Wei-Hui AU - Zhou WH AD - 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. FAU - Wang, Yan-Jiang AU - Wang YJ AD - Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China. FAU - Shen, Lin-Lin AU - Shen LL AD - Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China. FAU - Liu, Lu AU - Liu L AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China. FAU - Deng, Xiao-Juan AU - Deng XJ AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China. FAU - Wang, Xue-Feng AU - Wang XF AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China. FAU - Sun, Fei AU - Sun F AD - Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA. FAU - Chen, Guo-Jun AU - Chen GJ AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, China. LA - eng GR - R01 AG056060/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Brain JT - Brain : a journal of neurology JID - 0372537 RN - 0 (APP protein, human) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Benzofurans) RN - 0 (CL82198) RN - 0 (Eukaryotic Initiation Factors) RN - 0 (Matrix Metalloproteinase Inhibitors) RN - 0 (Morpholines) RN - 0 (Oligopeptides) RN - 0 (PS1 antigen) RN - 0 (eIF-4B) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) RN - EC 3.4.23.- (Aspartic Acid Endopeptidases) RN - EC 3.4.23.46 (BACE1 protein, human) RN - EC 3.4.24.- (MMP13 protein, human) RN - EC 3.4.24.- (Matrix Metalloproteinase 13) MH - Alzheimer Disease/genetics/*metabolism MH - Amyloid Precursor Protein Secretases/*metabolism MH - Amyloid beta-Protein Precursor/genetics MH - Animals MH - Aspartic Acid Endopeptidases/*metabolism MH - Benzofurans/*therapeutic use MH - Cells, Cultured MH - Cognitive Dysfunction/*drug therapy MH - Eukaryotic Initiation Factors/genetics MH - Gene Knockdown Techniques MH - Hippocampus/metabolism MH - Humans MH - Matrix Metalloproteinase 13/*metabolism MH - Matrix Metalloproteinase Inhibitors/*therapeutic use MH - Mice MH - Mice, Transgenic MH - Morpholines/*therapeutic use MH - Mutation MH - Oligopeptides/genetics MH - Phosphatidylinositol 3-Kinases/metabolism MH - Rats PMC - PMC6657286 EDAT- 2019/01/01 06:00 MHDA- 2019/08/21 06:00 PMCR- 2020/01/01 CRDT- 2019/01/01 06:00 PHST- 2018/04/18 00:00 [received] PHST- 2018/10/15 00:00 [accepted] PHST- 2019/01/01 06:00 [entrez] PHST- 2019/01/01 06:00 [pubmed] PHST- 2019/08/21 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 5263696 [pii] AID - awy305 [pii] AID - 10.1093/brain/awy305 [doi] PST - ppublish SO - Brain. 2019 Jan 1;142(1):176-192. doi: 10.1093/brain/awy305.