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The Journal of Neuroscience, January 19, 2005, 25(3):629-636; doi:10.1523/JNEUROSCI.4337-04.2005
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Neurobiology of Disease
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 
Margaret M. Racke,1,2
Laura I. Boone,1,3
Deena L. Hepburn,1,2
Maia Parsadainian,9
Matthew T. Bryan,1,2
Daniel K. Ness,1,4
Kathy S. Piroozi,1,4
William H. Jordan,1,3
Donna D. Brown,1,4
Wherly P. Hoffman,1,5
David M. Holtzman,7,8,9,10
Kelly R. Bales,1,2
Bruce D. Gitter,1,2
Patrick C. May,1,2
Steven M. Paul,1,6 and
Ronald B. DeMattos1,2
1Lilly Research Laboratories, Eli Lilly and Company,2 Neuroscience Discovery Research, Departments of 3Pathology, 4Toxicology, and 5Statistics, Lilly Corporate Center, and 6Departments of Pharmacology, Toxicology, and Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46285, 7Center for the Study of Nervous System Injury, 8Alzheimer's Disease Research Center, and Departments of 9Neurology and 10Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110
Passive immunization with an antibody directed against the N terminus of amyloid  (A) 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-A antibodies to deposited A 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 A, whereas 266, a central domain antibody, lacked affinity for deposited A. 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.
Key words: amyloid; CAA; immunotherapy; microhemorrhage; Alzheimer's disease; transgenic
Received Oct 19, 2004;
revised November 22, 2004;
accepted November 29, 2004.
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