Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP-2 and BACE-1 activities, and the modulation of APP trafficking

We previously demonstrated that membrane type 1 (MT1) matrix metalloproteinase (MMP) was up-regulated in the hippocampus of the model of transgenic mice bearing 5 familial mutations on human amyloid precursor protein (APP) and presenilin 1 of Alzheimer disease (AD), and that the proteinase increased the levels of amyloid β peptide (Aβ) and its APP C-terminal fragment of 99 aa in a heterologous cell system. Here we provide further evidence that MT1-MMP interacts with APP and promotes amyloidogenesis in a proteolytic-dependent manner in Swedish APP-expressing human embryonic kidney 293 (HEKswe) cells. MT1-MMP–mediated processing of APP releases a soluble APP fragment, sAPP95. This process partly requires the activation of endogenous MMP-2 but is independent of β-site APP cleaving enzyme 1 (BACE-1) or α-secretase activities. In contrast, MT1-MMP–mediated increase of Aβ levels involved BACE-1 activity and was inhibited by tissue inhibitor of MMP-2, a natural inhibitor of both MT1-MMP and MMP-2. Interestingly,...