title: Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology.
abstract: Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing beta-amyloid peptide (Abeta) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the Abeta peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against Abeta. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different Abeta epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of Abeta were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble Abeta was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for Abeta itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease.
authors.affiliation: Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA. frederique.bard@elan.com
authors.forename: Frédérique
authors.initials: F
authors.lastname: Bard
authors.forename: Robin
authors.initials: R
authors.lastname: Barbour
authors.forename: Catherine
authors.initials: C
authors.lastname: Cannon
authors.forename: Robert
authors.initials: R
authors.lastname: Carretto
authors.forename: Michael
authors.initials: M
authors.lastname: Fox
authors.forename: Dora
authors.initials: D
authors.lastname: Games
authors.forename: Teresa
authors.initials: T
authors.lastname: Guido
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hoenow
authors.forename: Kang
authors.initials: K
authors.lastname: Hu
authors.forename: Kelly
authors.initials: K
authors.lastname: Johnson-Wood
authors.forename: Karen
authors.initials: K
authors.lastname: Khan
authors.forename: Dora
authors.initials: D
authors.lastname: Kholodenko
authors.forename: Celeste
authors.initials: C
authors.lastname: Lee
authors.forename: Mike
authors.initials: M
authors.lastname: Lee
authors.forename: Ruth
authors.initials: R
authors.lastname: Motter
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.forename: Amanda
authors.initials: A
authors.lastname: Reed
authors.forename: Dale
authors.initials: D
authors.lastname: Schenk
authors.forename: Pearl
authors.initials: P
authors.lastname: Tang
authors.forename: Nicki
authors.initials: N
authors.lastname: Vasquez
authors.forename: Peter
authors.initials: P
authors.lastname: Seubert
authors.forename: Ted
authors.initials: T
authors.lastname: Yednock
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000517:prevention & control*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D000939:Epitopes; D010446:Peptide Fragments