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Abstract
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.
Document Type
Article
Publication Date
9-9-2011
Digital Object Identifier (DOI)
http://dx.doi.org/10.1186/1742-2094-8-115
Repository Citation
Wilcock, Donna M.; Morgan, Dave; Gordon, Marcia N.; Taylor, Tiffany L.; Ridnour, Lisa A.; Wink, David A.; and Colton, Carol A., "Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence" (2011). Sanders-Brown Center on Aging Faculty Publications. 17.
https://uknowledge.uky.edu/sbcoa_facpub/17
Notes/Citation Information
Published in Journal of Neuroinflammation, v. 8, 115.
© 2011 Wilcock et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.