Epitopes described in "MER5101, a novel Aβ1-15:DT conjugate vaccine, generates a robust anti-Aβ antibody response and attenuates Aβ pathology and cognitive deficits in APPswe/PS1ΔE9 transgenic mice."

Article Authors:Bin Liu; Jeffrey L Frost; Jing Sun; Hongjun Fu; Stephen Grimes; Peter Blackburn; Cynthia A Lemere
Article Title:MER5101, a novel Aβ1-15:DT conjugate vaccine, generates a robust anti-Aβ antibody response and attenuates Aβ pathology and cognitive deficits in APPswe/PS1ΔE9 transgenic mice.
Reference Detail
Reference ID:1025752
Abstract:Active amyloid- (A) immunotherapy is under investigation to prevent or treat early Alzheimer's disease (AD). In 2002, a Phase II clinical trial (AN1792) was halted due to meningoencephalitis in ∼6% of the AD patients, possibly caused by a T-cell-mediated immunological response. Thus, generating a vaccine that safely generates high anti-A antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of A1-15 peptide (a B-cell epitope fragment) conjugated to an immunogenic carrier protein, diphtheria toxoid (DT), and formulated in a nanoparticular emulsion-based adjuvant, was administered to 10-month-old APPswe/PS1E9 transgenic (Tg) and wild-type (Wt) mice. High anti-A antibody levels were observed in both vaccinated APPswe/PS1E9 Tg and Wt mice. Antibody isotypes were mainly IgG1 and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the A1-15:DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with A1-15 or A1-40/42 peptides, indicating a cellular immune response against DT while avoiding an A-specific T-cell response. Moreover, significant reductions in cerebral A plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101-vaccinated APPswe/PS1E9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PS1E9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic A conjugate vaccine, MER5101, shows promise for improving A vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.
Affiliations:Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Reference Type:Literature
PubMed ID:23595760
Journal:J Neurosci
Journal Volume:33
Article Pages:7027-37
Journal ISSN:1529-2401
Article Chemical List:Amyloid beta-Peptides;Amyloid beta-Protein Precursor;Culture Media, Conditioned;Cytokines;Diphtheria Toxoid;Glial Fibrillary Acidic Protein;Immunoglobulin G;PSEN1 protein, human;Peptide Fragments;Presenilin-1
Article MeSH List:Alzheimer Disease(complications; genetics); Amyloid beta-Peptides(immunology); Amyloid beta-Protein Precursor(genetics); Animals; Antibody Formation(immunology); CHO Cells(chemistry); Cell Proliferation(drug effects); Cerebral Cortex(immunology; metabolism); Cognition Disorders(etiology; immunology; pathology; therapy); Conditioning, Classical(physiology); Cricetinae; Culture Media, Conditioned(pharmacology); Cytokines(metabolism); Diphtheria Toxoid(immunology); Disease Models, Animal; Dose-Response Relationship, Immunologic; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Fear; Glial Fibrillary Acidic Protein(metabolism); Gliosis(immunology; therapy); Humans; Immunization(methods); Immunoglobulin G(blood; immunology); Immunoprecipitation; Maze Learning(physiology); Mice; Mice, Transgenic; Mutation(genetics); Peptide Fragments(immunology); Presenilin-1(genetics); Spleen(cytology); Statistics, Nonparametric; T-Lymphocytes(drug effects; immunology); Transfection
Curation Last Updated:2015-07-30 20:47:18