Regulation of matrix metalloproteinase 2 by oligomeric amyloid I2 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 I2 (AI2) and play important roles in the extracellular AI2 catabolism and clearance. On the other hand, MMPs could contribute to AD pathogenesis by compromising the blood brain barrier and promoting neurodegeneration. In the present study, we observed that oligomeric AI2 regulates MMP2 expression in a paradoxical manner. In rat primary astrocyte cultures, oligomeric AI2 down-regulated 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 IL-1I2 and TGFI2 were found in the brains of APP/PS1 mice. Our study suggests a complex regulation of MMP2 expression by oligomeric AI2 in astrocytes. While oligomeric AI2 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 AI2 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.