title: Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model.
abstract: Although anti-human β-amyloid (Aβ) immunotherapy clears brain β-amyloid plaques in Alzheimer's disease (AD), targeting additional brain plaque constituents to promote clearance has not been attempted. Endogenous murine Aβ is a minor Aβ plaque component in amyloid precursor protein (APP) transgenic AD models, which we show is ∼3%-8% of the total accumulated Aβ in various human APP transgenic mice. Murine Aβ codeposits and colocalizes with human Aβ in amyloid plaques, and the two Aβ species coimmunoprecipitate together from brain extracts. In the human APP transgenic mouse model Tg2576, passive immunization for 8 weeks with a murine-Aβ-specific antibody reduced β-amyloid plaque pathology, robustly decreasing both murine and human Aβ levels. The immunized mice additionally showed improvements in two behavioral assays, odor habituation and nesting behavior. We conclude that passive anti-murine Aβ immunization clears Aβ plaque pathology--including the major human Aβ component--and decreases behavioral deficits, arguing that targeting minor endogenous brain plaque constituents can be beneficial, broadening the range of plaque-associated targets for AD therapeutics.
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA. jmorales-corraliza@nki.rfmh.org
authors.forename: Jose
authors.initials: J
authors.lastname: Morales-Corraliza
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Mazzella
authors.forename: Jason D
authors.initials: JD
authors.lastname: Berger
authors.forename: Donald A
authors.initials: DA
authors.lastname: Wilson
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Wesson
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.forename: Efrat
authors.initials: E
authors.lastname: Levy
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001526:Behavioral Symptoms / Q000209:etiology / Q000276:immunology / Q000628:therapy; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009425:Nesting Behavior / Q000187:drug effects; D009812:Odorants; D000857:Olfaction Disorders / Q000209:etiology / Q000628:therapy; D053764:Presenilin-1 / Q000235:genetics; D018709:Statistics, Nonparametric
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; C508853:PSEN1 protein, human; D053764:Presenilin-1