title: 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.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Racke
authors.forename: Laura I
authors.initials: LI
authors.lastname: Boone
authors.forename: Deena L
authors.initials: DL
authors.lastname: Hepburn
authors.forename: Maia
authors.initials: M
authors.lastname: Parsadainian
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Bryan
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Ness
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Piroozi
authors.forename: William H
authors.initials: WH
authors.lastname: Jordan
authors.forename: Donna D
authors.initials: DD
authors.lastname: Brown
authors.forename: Wherly P
authors.initials: WP
authors.lastname: Hoffman
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gitter
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.forename: Ronald B
authors.initials: RB
authors.lastname: DeMattos
mesh_terms: 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
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor