Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence
1 University of Kentucky Sanders-Brown Center on Aging, Department of Physiology, Lexington KY 40536 USA
2 Duke University Medical Center, Department of Medicine, Division of Neurology, Durham NC 27710 USA
3 University of South Florida, Department of Molecular Pharmacology and Physiology, Tampa, FL 33612 USA
4 National Cancer Institute, Radiation Biology Branch, Bethesda, MD 20892 USA
Journal of Neuroinflammation 2011, 8:115 doi:10.1186/1742-2094-8-115Published: 9 September 2011
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.
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.
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.
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.