title: An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome.
abstract: In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer's disease (AD). At present, no treatment targets Aβ-related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1-15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS.
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Belichenko
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Rime
authors.initials: R
authors.lastname: Madani
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Lorianne
authors.initials: L
authors.lastname: Rey-Bellet
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Pihlgren
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Becker
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Adeline
authors.initials: A
authors.lastname: Plassard
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Vuillermot
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Giriens
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Nosheny
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kleschevnikov
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Janice S
authors.initials: JS
authors.lastname: Valletta
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Sara K S
authors.initials: SK
authors.lastname: Bengtsson
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Linke
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford Medical School, Stanford, California, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Maloney
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: David T
authors.initials: DT
authors.lastname: Hickman
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Pedro
authors.initials: P
authors.lastname: Reis
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Granet
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Dorin
authors.initials: D
authors.lastname: Mlaki
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Lopez-Deber
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Long
authors.initials: L
authors.lastname: Do
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Nishant
authors.initials: N
authors.lastname: Singhal
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Pearn
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: AC Immune SA, Lausanne, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000378:metabolism; D001284:Atrophy; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D059329:Cholinergic Neurons / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications* / Q000188:drug therapy*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications* / Q000188:drug therapy*; D005786:Gene Expression Regulation; D006470:Hemorrhage / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008297:Male; D008568:Memory; D008822:Mice, Transgenic; D012686:Septal Nuclei / Q000473:pathology; D014611:Vaccination; D014612:Vaccines / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D015415:Biomarkers; D014612:Vaccines