The Regulated Mechanisms Of MMP13 On BACE1 And The Therapeutic Effects On Alzheimer’s Disease

The ?-amyloid protein(A ?) has been the important pathogenic substances of Alzheimer’s disease(AD). Beta-site APP-cleaving enzyme 1(BACE1), the key rate-limiting enzyme of A? generation, has become the main target of current drug research. In the previous study, we found that MMP13 inhibitor could significantly inhibit luciferase activity of BACE1 promoter. On this basis, we verify the effect of MMP13 on BACE1 and its regulatory mechanisms at the cellular level; and the APP/PS1 mouse’s change of behavior after the treatment of MMP13 inhibitor. In vitro, we found that MMP13 was closely related to the BACE1 expression. MMP13 inhibition regulated the translation of BACE1 by RTK-PI3K-eIF4 B signal pathway, but not regulated the transcription and degradation pathways of BACE1. In vivo, we found that in the hippocampus of 7 months APP / PS1 mice, the expression of MMP13 was significantly more than the one of control group. After treatment with MMP13 inhibitor to APP/PS1 mice for2 months, the expression of BACE1 in the treatment groups wassignificantly reduced, the β degradative pathway of the APP was suppressed, Aβ plaques in brain of the treatment groups were also significantly reduced by immunohistochemistry. The learning and memory abilities of drug-treated groups APP / PS1 mice could be significantly improved by Morris water maze and the fear conditioning assay. These results suggest that MMP13 may be involved in the pathogenesis development of AD though regulating the translation of BACE1 to affect the production of A?. In summary, MMP13 inhibition maybe the potential targets of Alzheimer’s disease.