Abstract T P221: Anti-amyloid Immunotherapy Results in Exacerbation of Cerebrovascular Disease Through Activation of Matrix Metalloproteinases
Cerebrovascular disease is frequently co-morbid with Alzheimer’s disease (AD) and we hypothesize this co-morbidity could complicate the development of disease-modifying therapies. The amyloid-beta (Aβ) peptide has been the intense focus of therapeutic development for the treatment of AD. One therapeutic approach uses passive immunization against Aβ using anti-Aβ antibodies. We further hypothesize that inflammation mediated activation of MMP9 and MMP2 lead to the exacerbation of cerebrovascular pathologies following immunotherapy. To test our hypothesis we took aged 21 month old APP transgenic mice (PDAPP mice) that have cerebral amyloid angiopathy (CAA) and disruptions of the blood-brain barrier and administered anti-Aβ antibody or control IgG2a for 8 weeks at a dose of 12.5mg/kg. Expression of the MMP2 and MMP9 families were measured by qPCR and Western blot, total Aβ, CAA and albumin for vasogenic edema were measured using immunohistochemistry, and finally, microhemorrhages were assessed with Prussian blue staining.
Treatment with the anti-Aβ antibody resulted in significantly decreased Aβ in the frontal cortex and hippocampus. Further, we found increased microhemorrhage associated with increased gene expression of MMP9, MMP2 and MMP14 (the activator of MMP2). Assessment of vasogenic edema, as well as CAA and inflammatory states is currently ongoing.
Overall, while anti-Aβ treatment leads to decreased Aβ, cerebrovascular pathologies, most notably microhemorrhages, are increased by immunotherapy. This increased microhemorrhage is associated with increased MMP2 and MMP9 expression. These data suggest that co-morbidity of cerebrovascular pathologies with AD will significantly impair efficacy of therapeutics for AD and could potentially lead to adverse events.
- Cerebral amyloid angiopathy
- Cerebrovascular disorders
- Extracellular matrix
- Vascular cognitive impairment
Author Disclosures: E.M. Weekman: None. T.L. Sudduth: None. D.M. Wilcock: None.
- © 2015 by American Heart Association, Inc.