Short amyloid-beta immunogens show strong immunogenicity and avoid stimulating pro-inflammatory pathways in bone marrow-derived dendritic cells from C57BL/6J mice in vitro.

Amyloid beta peptide 1-15 (Aß1-15) and its derivatives have attracted the attention of the scientific community as candidate vaccines for Alzheimer's disease (AD) immunotherapy. Recent studies suggested that Aß1-42 modulated the immune system by inducing pro-inflammatory dendritic cells (DCs) with reduced antigen-presenting function. However, it remains elusive how Aß1-15 impacts DCs function. We therefore investigated the modulation by short Aß peptides of DCs from C57Bl/6J mice. Two new immunogens, a tandem repeat of two-lysine-linked Aß1-15 sequences with or without an addition of a RGD motif, were tested. Chemotaxis, endocytosis, antigen presenting function and producing cytokines were measured. Both peptides increased migration/endocytosis of immature DCs and MHC II molecule expression/alloreactive T cell activation in TNF-α-matured DCs. In addition, they exhibited decreased production of Th1/Th2 cytokines and pro-inflammatory cytokines. Overall, the two peptides demonstrated strong immunogenicity but did not stimulate pro-inflammatory pathways. These results support the use of short Aß immunogens in AD immunotherapy.

Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains.

Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Overexpression of tumor necrosis factor-α (TNF-α) occurs in the AD brain. Recent clinical studies have shown that the anti-TNF-α therapy improves cognition function of AD patients rapidly. However, the underlying mechanism remains elusive. The present study investigates the effects of intracerebroventricular injection of the monoclonal TNF-α antibody, Infliximab, on the pathological features of AD in the APP/PS1 double transgenic mice. We found that Infliximab administration reduced the levels of TNF-α, amyloid plaques, and tau phosphorylation as early as three days after daily injection of 150 µg Infliximab for three days. The number of CD11c-positive dendritic-like cells and the expression of CD11c were found to be increased concurrently after Infliximab injection. These data suggested that the CD11c-positive dendritic-like cells might contribute to the Infliximab-induced reduction of AD-like pathology. Furthermore, our results support the use of anti-TNF-α for the treatment of AD.