Degradation of Soluble and Fibrillar Amyloid β-Protein by Matrix Metalloproteinase (MT1-MMP) in Vitro

The progressive accumulation of beta-amyloids (A beta) in senile plaques and in the cerebral vasculature is the hallmark of Alzheimer's disease and related disorders. Degradation of A beta by specific proteolytic enzymes is an important process that regulates its levels in brain. Matrix metalloproteinase 2 (MMP2) was shown to be expressed in reactive astrocytes surrounding amyloid plaques and may contribute to A beta degradation. Membrane type 1 (MT1) MMP is the physiological activator For the zymogen pro-MMP2. Here, we show that, in addition to MMP2, its activator MT1-MMP is also expressed in reactive astrocytes in regions with amyloid deposits in transgenic mice. Using a Cos-1 cell expression system, we demonstrated that MT1-MMP can degrade exogenous A beta 40 and A beta 42. A purified soluble form of MT1-MMP degraded both soluble and fibrillar A beta peptides in a time-dependent manner, yielding specific degradation products. Mass spectrometry analysis identified multiple MT1-MMP cleavage sites on soluble A beta 40 and A beta 42. MT1-MMP-mediated A beta degradation was inhibited with the general MMP inhibitor GM6001 or the specific MT1-MMP inhibitor tissue inhibitor of metalloproteinases 2. Furthermore, in situ experiments showed that purified MT1-MMP degraded parenchymal fibrillar amyloid plaques that form in the brains of A beta precursor protein transgenic mice. Together, these findings indicate that MT1-MMP possesses A beta degrading activity in vitro.