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 beta.
Passive immunization with an antibody directed against the N terminus of amyloid beta (Abeta) 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-Abeta antibodies to deposited Abeta 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 Abeta, whereas 266, a central domain antibody, lacked affinity for deposited Abeta. 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.
Racke
Margaret M
MM
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Boone
Laura I
LI
Hepburn
Deena L
DL
Parsadainian
Maia
M
Bryan
Matthew T
MT
Ness
Daniel K
DK
Piroozi
Kathy S
KS
Jordan
William H
WH
Brown
Donna D
DD
Hoffman
Wherly P
WP
Holtzman
David M
DM
Bales
Kelly R
KR
Gitter
Bruce D
BD
May
Patrick C
PC
Paul
Steven M
SM
DeMattos
Ronald B
RB
D000375:Aging / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000915:Antibody Affinity; D016657:Cerebral Amyloid Angiopathy / Q000276:immunology* / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007116:Immunization, Passive / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor