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

Journal of Neuroinflammation

Carol A Colton³  David A Wink²  Lisa A Ridnour²  Tiffany L Taylor¹  Marcia N Gordon⁴  Dave Morgan⁴  Donna M Wilcock³ 

[1]University of Kentucky Sanders-Brown Center on Aging, Department of Physiology, Lexington KY 40536 USA

[2]National Cancer Institute, Radiation Biology Branch, Bethesda, MD 20892 USA

[3]Duke University Medical Center, Department of Medicine, Division of Neurology, Durham NC 27710 USA

[4]University of South Florida, Department of Molecular Pharmacology and Physiology, Tampa, FL 33612 USA

关键词: Alzheimer's disease;    transgenic mouse;    cerebral amyloid angiopathy;    amyloid;    microhemorrhage;    inflammation;    matrix metalloproteinases;    Immunotherapy;   

Others  :  1213132
DOI  :  10.1186/1742-2094-8-115

 received in 2011-06-24, accepted in 2011-09-09,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Wilcock et al; licensee BioMed Central Ltd.

【 图 表 】

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