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

Background: anti-aβ 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-aβ immunotherapy studies. the first was a passive immunization study in which we examined 22 month old appsw mice that had received anti-aβ 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 aβ vaccination for 4 months.results: there is a significant activation of the mmp2 and mmp9 proteinase degradation systems by anti-aβ 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. © 2011 wilcock et al; licensee biomed central ltd.