Regulation of matrix metalloproteinase 2 by oligomeric amyloid β protein

Matrix metalloproteinases (MMPs) are a group of proteinases that degrade components of the extracellular matrix (ECM). There is increasing evidence for a link between the activation of MMPs and Alzheimer's disease (AD) pathogenesis, in which both beneficial and detrimental actions of MMPs have been suggested. It has been demonstrated that MMPs could degrade amyloid beta (A beta) and play important roles in the extracellular A beta catabolism and clearance. On the other hand, MMPs could contribute to AD pathogenesis by compromising the blood brain bather and promoting neurodegeneration. In the present study, we observed that oligomeric A beta regulates MMP2 expression in a paradoxical manner. In rat primary astrocyte cultures, oligomeric A beta downregulated MMP2 transcription and reduced its extracellular activity. However, in a widely used mouse model for AD, immunohistochemistry demonstrated an increase of MMP2 expression in astrocytes surrounding senile plaques in APP/PS1 transgenic mice brains. Using real-time PCR, we found that the MMP2 mRNA level was elevated in APP/PS1 transgenic mice brains. In addition, elevated mRNA levels of MMP stimulating cytokines such as and TGF beta were found in the brains of APP/PS1 mice. Our study suggests a complex regulation of MMP2 expression by oligomeric A beta in astrocytes. While oligomeric A beta directly down-regulates MMP2 expression and activation in astrocytes, it induces production of proinflammatory cytokines which could serve as strong stimulators for MMP2. Therefore, the ultimate outcome of the oligomeric A beta on MMP2 activation in astrocytes might be the combination of its direct inhibitory action on astrocyte MMP2 expression and the secondary action of inducing inflammatory cytokines. (C) 2011 Elsevier B.V. All rights reserved.