title: Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence.
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.
authors: University of Kentucky Sanders-Brown Center on Aging, Department of Physiology, Lexington, KY 40536, USA. donna.wilcock@uky.edu
authors: Donna M
authors: DM
authors: Wilcock
authors: Dave
authors: D
authors: Morgan
authors: Marcia N
authors: MN
authors: Gordon
authors: Tiffany L
authors: TL
authors: Taylor
authors: Lisa A
authors: LA
authors: Ridnour
authors: David A
authors: DA
authors: Wink
authors: Carol A
authors: CA
authors: Colton
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000276:immunology; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9