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An anti-β-amyloid vaccine for treating cognitive deficits in a mouse model of Down syndrome


Year of Publication:
Contact PI Name:
Andreas Muhs
Contact PI Affiliation:
AC Immune SA, Lausanne, Switzerland
Pavel V. Belichenko, Rime Madani, Lorianne Rey-Bellet, Maria Pihlgren, Ann Becker, Adeline Plassard, Stephanie Vuillermot, Valérie Giriens, Rachel L. Nosheny, Alexander M. Kleschevnikov, Janice S. Valletta, Sara K. S. Bengtsson, Gordon R. Linke
Primary Reference (PubMED ID):
Funding Source:
AC Immune SA
Study Goal and Principal Findings:

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. This study 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(active)
Therapeutic Agent:
beta Amyloid Peptide 1-15
Therapeutic Target:
beta Amyloid Peptide

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Novel Object Recognition Test (NORT)
Fear Conditioning Response
Motor Function
Locomotor Activity
Activated Astrocytes
Activated Microglia
Lymphocytic Infiltration
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Interferon (IFN) gamma
Plasma-Interferon (IFN) gamma
Tumor Necrosis Factor alpha (TNF alpha)
Plasma-Tumor Necrosis Factor alpha (TNF alpha)
Interleukin 1 beta (IL-1 beta)
Plasma-Interleukin-1 beta (IL-1 beta)
Interleukin 6 (IL-6)
Plasma-Interleukin-6 (IL-6)
Amyloid Precursor Protein (APP) mRNA
Amyloid Precursor Protein (APP)
Proinflammatory Markers
Choline Acetyltransferase (ChAT)
Glial Fibrillary Acidic Protein (GFAP)
Anti-beta Amyloid IgG Production
Antibody Target Specificity
Anti-beta Amyloid Antibody Titers
Plasma-Proinflammatory Markers
Antibody Concentration-Plasma
Target Engagement (Reduction beta Amyloid Peptide 40-Brain)
Target Engagement (Reduction beta Amyloid Peptide 42-Brain)
Body Weight