Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

摘要

In Alzheimer's disease (AD) the accumulation of pathological forms of the beta-amyloid (Aβ) peptide are believed to be causal factors in the neurodegeneration that results in the loss of cognitive function in patients. Anti-Aβ antibodies have been shown to reduce Aβ 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 Aβ 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 Aβ 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-Aβ 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.