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

J Neurosci. 2006 May 3;26(18):4717-28. doi: 10.1523/JNEUROSCI.0381-06.2006.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / immunology*
  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / immunology*
  • Amyloid beta-Peptides / 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
  • Learning Disabilities / therapy*
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / immunology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Time Factors
  • Vaccines

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antibodies
  • Bacterial Toxins
  • Cytokines
  • Enterotoxins
  • Escherichia coli Proteins
  • Peptide Fragments
  • Vaccines
  • heat-labile enterotoxin, E coli