Abeta-immunotherapy for Alzheimer's disease using mannan-amyloid-Beta peptide immunoconjugates.

Abstract

In Alzheimer's disease (AD) the accumulation of pathological forms of the beta-amyloid (Abeta) peptide are believed to be causal factors in the neurodegeneration that results in the loss of cognitive function in patients. Anti-Abeta antibodies have been shown to reduce Abeta levels in transgenic mouse models of AD and in AN-1792 clinical trial on AD patients; however, the clinical trial was halted when some patients developed meningoencephalitis. Theories on the cause of the adverse events include proinflammatory "primed patients," a Th1-inducing adjuvant, and Abeta autoreactive T cells. New immunotherapy approaches are being developed to eliminate these putative risk factors. Mannan, which is recognized by pattern recognition receptors of the innate immune system, can be utilized as a molecular adjuvant to promote a Th2-mediated immune response to conjugated B cell epitopes. The N-terminus of Abeta was conjugated to mannan, and used to immunize mice with low concentrations of immunoconjugate, without a conventional adjuvant. Mannan induced a significant and highly polarized toward Th2 phenotype anti-Abeta antibody response not only in BALB/c, but also in B6SJL F1 mice. New preclinical trials in AD mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse immune response that occurred in the first clinical trial.

• Authors: Anahit Ghochikyan, Irina Petrushina, Andrew Lees, Vitaly Vasilevko, Nina Movsesyan, Adrine Karapetyan, Michael G Agadjanyan, David H Cribbs
• Journal: DNA and cell biology (DNA Cell Biol) Vol. 25 Issue 10 Pg. 571-80 (Oct 2006) ISSN: 1044-5498 [Print] United States
• PMID: 17132088 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AN-1792
• Amyloid beta-Peptides
• Epitopes, B-Lymphocyte
• Peptides

Topics

• Alzheimer Disease (immunology, therapy)
• Amyloid beta-Peptides (chemistry, pharmacology)
• Animals
• Cell Proliferation
• Disease Models, Animal
• Epitopes, B-Lymphocyte (chemistry)
• Immunotherapy (methods)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Peptides (chemistry)
• Protein Structure, Tertiary
• Risk Factors