BACE1 is the rate-limiting enzyme in amyloid- generation. Zhu et al. report that selective inhibition of matrix metallopeptidase 13 (MMP13) decreases BACE1 levels and amyloid- load, and improves cognitive performance in a mouse model of Alzheimers disease. MMP13 inhibition may have therapeutic potential via translational regulation of BACE1.MMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimers 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 (-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5 untranslated region (5UTR). 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 5UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimers disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid- precursor protein processing, amyloid- load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimers disease, via the translational regulation of BACE1.