Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence

Background: Anti-A beta immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD) currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s) by which they occur. Methods: We have examined the matrix metalloproteinase (MMP) protein degradation system in two previously published anti-A beta immunotherapy studies. The first was a passive immunization study in which we examined 22 month old APPSw mice that had received anti-A beta antibodies for 1, 2 or 3 months. The second is an active vaccination study in which we examined 16 month old APPSw/NOS2-/- mice treated with A beta vaccination for 4 months. Results: There is a significant activation of the MMP2 and MMP9 proteinase degradation systems by anti-A beta immunotherapy, regardless of whether this is delivered through active vaccination or passive immunization. We have characterized this activation by gene expression, protein expression and zymography assessment of MMP activity. Conclusions: Since the MMP2 and MMP9 systems are heavily implicated in the pathophysiology of intracerbral hemorrhage, these data may provide a potential mechanism of microhemorrhage due to immunotherapy. Increased activity of the MMP system, therefore, is likely to be a major factor in increased microhemorrhage occurrence.