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

Autor: Carol A. Colton, Tiffany L. Taylor, Lisa A. Ridnour, Dave Morgan, David A. Wink, Marcia N. Gordon, Donna M. Wilcock
Rok vydání: 2011
Předmět:
Neurology
medicine.medical_treatment
Nitric Oxide Synthase Type II
Disease
lcsh:RC346-429
Mice
0302 clinical medicine
microhemorrhage
0303 health sciences
General Neuroscience
matrix metalloproteinases
amyloid
Alzheimer's disease
3. Good health
Matrix Metalloproteinase 9
Cerebrovascular Circulation
Matrix Metalloproteinase 2
Cerebral amyloid angiopathy
Immunotherapy
medicine.symptom
medicine.medical_specialty
Immunology
Inflammation
Mice
Transgenic
03 medical and health sciences
Cellular and Molecular Neuroscience
Alzheimer Disease
medicine
Animals
Humans
Adverse effect
cerebral amyloid angiopathy
lcsh:Neurology. Diseases of the nervous system
030304 developmental biology
Cerebral Hemorrhage
Amyloid beta-Peptides
business.industry
Microcirculation
Research
medicine.disease
Clinical trial
Enzyme Activation
transgenic mouse
Disease Models
Animal
inflammation
business
030217 neurology & neurosurgery
Zdroj: Journal of Neuroinflammation
Journal of Neuroinflammation, Vol 8, Iss 1, p 115 (2011)
ISSN: 1742-2094
Popis: 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.
Databáze: OpenAIRE
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