title: Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis.
abstract: Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta peptide (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta42 in humans was discontinued because a few patients developed significant meningo-encephalitic cellular inflammatory reactions. Here we show that beneficial effects in mice arise from antibodies selectively directed against residues 4-10 of Abeta42, and that these antibodies inhibit both Abeta fibrillogenesis and cytotoxicity without eliciting an inflammatory response. These findings provide the basis for improved immunization antigens as well as attempts to design small-molecule mimics as alternative therapies.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada. j.mclaurin@utoronto.ca
authors.forename: J
authors.initials: J
authors.lastname: McLaurin
authors.forename: R
authors.initials: R
authors.lastname: Cecal
authors.forename: M E
authors.initials: ME
authors.lastname: Kierstead
authors.forename: X
authors.initials: X
authors.lastname: Tian
authors.forename: A L
authors.initials: AL
authors.lastname: Phinney
authors.forename: M
authors.initials: M
authors.lastname: Manea
authors.forename: J E
authors.initials: JE
authors.lastname: French
authors.forename: M H L
authors.initials: MH
authors.lastname: Lambermon
authors.forename: A A
authors.initials: AA
authors.lastname: Darabie
authors.forename: M E
authors.initials: ME
authors.lastname: Brown
authors.forename: C
authors.initials: C
authors.lastname: Janus
authors.forename: M A
authors.initials: MA
authors.lastname: Chishti
authors.forename: P
authors.initials: P
authors.lastname: Horne
authors.forename: D
authors.initials: D
authors.lastname: Westaway
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
authors.forename: H T J
authors.initials: HT
authors.lastname: Mount
authors.forename: M
authors.initials: M
authors.lastname: Przybylski
authors.forename: P
authors.initials: P
authors.lastname: St George-Hyslop
mesh_terms: D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D001921:Brain / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000906:Antibodies