title: Transgenic expression of β1 antibody in brain neurons impairs age-dependent amyloid deposition in APP23 mice.
abstract: Heterologous expression of the functional amyloid beta (Aβ) antibody β1 in the central nervous system was engineered to maximize antibody exposure in the brain and assess the effects on Aβ production and accumulation in these conditions. A single open reading frame encoding the heavy and light chains of β1 linked by the mouth and foot virus peptide 2A was expressed in brain neurons of transgenic mice. Two of the resulting BIN66 transgenic lines were crossed with APP23 mice, which develop severe central amyloidosis. Brain concentrations at steady-state 5 times greater than those found after peripheral β1 administration were obtained. Similar brain and plasma β1 concentrations indicated robust antibody efflux from the brain. In preplaque mice, β1 formed a complex with Aβ that caused a modest Aβ increase in brain and plasma. At 11 months of age, β1 expression reduced amyloid by 97% compared with age-matched APP23 mice. Interference of β1 with β-secretase cleavage of amyloid precursor protein was relatively small. Our data suggest that severely impaired amyloid formation was primarily mediated by a complex of β1 with soluble Aβ, which might have prevented Aβ aggregation or favored transport out of the brain.
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland. Electronic address: paganepa@bluewin.ch.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.forename: Julia
authors.initials: J
authors.lastname: Reichwald
authors.forename: Dorothee
authors.initials: D
authors.lastname: Bleckmann
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.forename: Domenico
authors.initials: D
authors.lastname: Ammaturo
authors.forename: Carmen
authors.initials: C
authors.lastname: Barske
authors.forename: Simone
authors.initials: S
authors.lastname: Danner
authors.forename: Maurizio
authors.initials: M
authors.lastname: Molinari
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Papin
authors.forename: Sabine
authors.initials: S
authors.lastname: Rabe
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000502:physiology*; D001921:Brain / Q000276:immunology* / Q000378:metabolism*; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies
keywords: APP processing; Alzheimer's disease; Aβ deposition; Aβ efflux; Brain amyloid; Immunotherapy