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PMID: 16672644 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer's disease mouse model in the absence of an Abeta-specific cellular immune response.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 26 ·No. 18 ·2006-05-03 ·Pages 4717-28

Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA

Abstract

Amyloid-beta (Abeta) immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). A clinical trial using active immunization with Abeta1-42 was suspended after approximately 6% of patients developed meningoencephalitis, possibly because of a T-cell reaction against Abeta. Nevertheless, beneficial effects were reported in antibody responders. Consequently, alternatives are required for a safer vaccine. The Abeta1-15 sequence contains the antibody epitope(s) but lacks the T-cell reactive sites of full-length Abeta1-42. Therefore, we tested four alternative peptide immunogens encompassing either a tandem repeat of two lysine-linked Abeta1-15 sequences (2xAbeta1-15) or the Abeta1-15 sequence synthesized to a cross-species active T1 T-helper-cell epitope (T1-Abeta1-15) and each with the addition of a three-amino-acid RGD (Arg-Gly-Asp) motif (R-2xAbeta1-15; T1-R-Abeta1-15). High anti-Abeta antibody titers were observed in wild-type mice after intranasal immunization with R-2xAbeta1-15 or 2xAbeta1-15 plus mutant Escherichia coli heat-labile enterotoxin LT(R192G) adjuvant. Moderate antibody levels were induced after immunization with T1-R-Abeta1-15 or T1-Abeta1-15 plus LT(R192G). Restimulation of splenocytes with the corresponding immunogens resulted in moderate proliferative responses, whereas proliferation was absent after restimulation with full-length Abeta or Abeta1-15. Immunization of human amyloid precursor protein, familial AD (hAPP(FAD)) mice with R-2xAbeta1-15 or 2xAbeta1-15 resulted in high anti-Abeta titers of noninflammatory T-helper 2 isotypes (IgG1 and IgG2b), a lack of splenocyte proliferation against full-length Abeta, significantly reduced Abeta plaque load, and lower cerebral Abeta levels. In addition, 2xAbeta1-15-immunized hAPP(FAD) animals showed improved acquisition of memory compared with vehicle controls in a reference-memory Morris water-maze behavior test that approximately correlated with anti-Abeta titers. Thus, our novel immunogens show promise for future AD vaccines.

MeSH Terms
Alzheimer Disease/complications,immunology,physiopathology,therapy Amyloid beta-Peptides/administration & dosage,genetics,immunology,metabolism Amyloid beta-Protein Precursor/genetics Analysis of Variance Animals Antibodies/blood Antibody Specificity Bacterial Toxins/immunology Behavior, Animal Biophysical Phenomena Biophysics Brain Chemistry Cell Proliferation Cytokines/metabolism Disease Models, Animal Enterotoxins/immunology Enzyme-Linked Immunosorbent Assay/methods Epitope Mapping/methods Escherichia coli Proteins/immunology Immunization, Secondary Immunohistochemistry/methods Learning Disabilities/etiology,therapy Male Maze Learning/physiology Mice Mice, Inbred C57BL Mice, Transgenic Peptide Fragments/administration & dosage,immunology T-Lymphocytes/immunology,metabolism Time Factors Vaccines
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Antibodies Bacterial Toxins Cytokines Enterotoxins Escherichia coli Proteins Peptide Fragments Vaccines heat-labile enterotoxin, E coli
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Maier Marcel
Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Seabrook Timothy J
Lazo Noel D
Jiang Liying
Das Pritam
Janus Christopher
Lemere Cynthia A
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0381-06.2006
Published
2006-05-03
Pages
4717-28
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6674171
Subset
IM
Grants
NIA NIH HHS · AG20159 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.0381-06.2006 PMC Full Text View journal details
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