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

Brain : a journal of neurology (2019-01-01)
Bing-Lin Zhu, Yan Long, Wei Luo, Zhen Yan, Yu-Jie Lai, Li-Ge Zhao, Wei-Hui Zhou, Yan-Jiang Wang, Lin-Lin Shen, Lu Liu, Xiao-Juan Deng, Xue-Feng Wang, Fei Sun, Guo-Jun Chen
RESUMEN

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.

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Anti-Amyloid Precursor Protein, C-Terminal antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
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FGF/PDGF/VEGF RTK Inhibitor, The FGF/PDGF/VEGF RTK Inhibitor, also referenced under CAS 144335-37-5, controls the biological activity of FGF/PDGF/VEGF RTK. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.