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

Donna M. Wilcock, Dave Morgan, Marcia N. Gordon, Tiffany L. Taylor, Lisa A. Ridnour, David A. Wink, Carol A. Colton

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish
Article number115
JournalJournal of Neuroinflammation
Volume8
DOIs
StatePublished - Sep 9 2011

Bibliographical note

Funding Information:
These studies were funded by NIH grants AG030942 (DMW), AG15490 (MNG), AG18478 (DM), AG031845 (CAC), AG19740 (CAC), Alzheimer’s Association grant IIRG-07-59802 (CAC) and Alzheimer’s Association grant NIRG-09-13302 (DMW).

Keywords

  • Alzheimer's disease
  • Amyloid
  • Cerebral amyloid angiopathy
  • Immunotherapy
  • Inflammation
  • Matrix metalloproteinases
  • Microhemorrhage
  • Transgenic mouse

ASJC Scopus subject areas

  • Neuroscience (all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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