Exacerbation of Cerebral Amyloid Angiopathy-Associated Microhemorrhage in Amyloid Precursor Protein Transgenic Mice by Immunotherapy Is Dependent on Antibody Recognition of Deposited Forms of Amyloid β

• Published in: The Journal of neuroscience Vol. 25; no. 3; pp. 629 - 636
• Main Authors: Racke, Margaret M., Boone, Laura I., Hepburn, Deena L., Parsadainian, Maia, Bryan, Matthew T., Ness, Daniel K., Piroozi, Kathy S., Jordan, William H., Brown, Donna D., Hoffman, Wherly P., Holtzman, David M., Bales, Kelly R., Gitter, Bruce D., May, Patrick C., Paul, Steven M., DeMattos, Ronald B.
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 19.01.2005
• Subjects: Aging - metabolism; Amyloid beta-Peptides - immunology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Antibody Affinity; Cerebral Amyloid Angiopathy - immunology; Cerebral Amyloid Angiopathy - metabolism; Cerebral Hemorrhage - immunology; Cerebral Hemorrhage - metabolism; Female; Immunization, Passive - adverse effects; Male; Mice; Mice, Transgenic; Neurobiology of Disease
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4337-04.2005

Passive immunization with an antibody directed against the N terminus of amyloid β (Aβ) has recently been reported to exacerbate cerebral amyloid angiopathy (CAA)-related microhemorrhage in a transgenic animal model. Although the mechanism responsible for the deleterious interaction is unclear, a direct binding event may be required. We characterized the binding properties of several monoclonal anti-Aβ antibodies to deposited Aβ in brain parenchyma and CAA. Biochemical analyses demonstrated that the 3D6 and 10D5, two N-terminally directed antibodies, bound with high affinity to deposited forms of Aβ, whereas 266, a central domain antibody, lacked affinity for deposited Aβ. To determine whether 266 or 3D6 would exacerbate CAA-associated microhemorrhage, we treated aged PDAPP mice with either antibody for 6 weeks. We observed an increase in both the incidence and severity of CAA-associated microhemorrhage when PDAPP transgenic mice were treated with the N-terminally directed 3D6 antibody, whereas mice treated with 266 were unaffected. These results may have important implications for future immune-based therapeutic strategies for Alzheimer's disease.