Matrix metalloprotease-9 inhibition improves amyloid beta-mediated cognitive impairment and neurotoxicity in mice

In Alzheimer's disease (AD), the expression of matrix metalloproteases (MMPs), which are capable of degrading extracellular matrix proteins, is increased in the brain. Previous studies with cultured glial cells have demonstrated that amyloid beta (Abeta) protein can induce the expression of MMPs, which could be involved in the degradation of Abeta. In the present study, we investigated the role of MMP-2 and MMP-9 in cognitive impairment induced by the injection of Abeta in mice. The intracerebroventricular injection of Abeta25-35, Abeta1-40, and Abeta1-42, but not Abeta40-1, transiently increased MMP-9, but not MMP-2, activity and protein expression in the hippocampus. Immunohistochemistry revealed the expression of MMP-9 to be increased in both neurons and glial cells in the hippocampus after Abeta treatment. The Abeta-induced cognitive impairment in vivo as well as neurotoxicity in vitro was significantly alleviated in MMP-9 homozygous knockout mice and by treatment with MMP inhibitors. These results suggest the increase in MMP-9 expression in the hippocampus to be involved in the development of cognitive impairment induced by Abeta1-40. Thus, specific inhibitors of MMP-9 may have therapeutic potential for the treatment of AD. Our findings suggest that, as opposed to expectations based on previous findings, MMP-9 plays a causal role in Abeta-induced cognitive impairment and neurotoxicity.