An Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-β.

Background: Aging is considered the most important risk factor for Alzheimer's disease (AD). Recent research supports the theory that immunotherapy targeting the "oligomeric" forms of amyloid-beta (A beta) may halt the progression of AD. However, previous clinical trial of the vaccine against A beta, called AN1792, was suspended due to cases of meningoencephalitis in patients. Objective: To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer A beta and prevent an autoimmune response. Methods: Double transgenic APP(swe)/PS1(Delta E9) (Tg) and C57BL/6J control mice were used in this study. Cytokine expression profile detection, characterization of antisera, brain GSK-3 beta, LC3 expression, and spatial working memory testing before and post-vaccination were obtained. Results: Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type A beta. The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric A beta-specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC's natural immunomodulatory properties. Conclusion: The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of A beta are the toxic species to neurons, the E22W42 antibody's specificity for these "oligomeric" A beta species could provide the opportunity to produce some clinical benefits in AD subjects.