Oligomeric amyloid‐beta 1–42 inhibits antigen presentation

Abstract

AbstractBackgroundBeyond microglia, the involvement of other immune cell types and immune functions in Alzheimer’s disease (AD) is not well understood. Here, we investigated the potential immunomodulatory properties in vivo and in vitro of oligomeric species of beta‐amyloid‐peptide (Aβ) on microglia and other putative antigen presenting cells (APCs).MethodsWe used multicolour flow‐cytometry, confocal microscopy and MSD biochemical analysis to characterise amyloid deposition and brain immunephenotype of APP‐PS1‐dE9 mice of 3, 6, 12 and 20 months of age. Next, we applied a customised in vitro systems (using OT‐II ovalbumin‐specific transgenic CD4+ T cells and ovalbumin as antigen) to study the effect of recombinant, oligomeric preparations of human Aβ1‐42 on antigen presentation by primary dendritic cells. Finally, via RNAseq, we investigated the effect of oligomeric Aβ 1‐42 on the transcriptome of primary dendritic cells.ResultsWe show that, in the APP‐PS1‐dE9 mouse model, the deposition of the first beta‐amyloid plaques at 6 months of age is accompanied by a significant reduction in MHC class II surface levels on brain APCs, suggesting impaired antigen presentation capability induced by beta‐amyloid. This hypothesis was confirmed by our in vitro experiments, using the prototypical antigen presenting cells, primary bone‐marrow derived dendritic cells. Incubation with a preparation containing various forms of oligomeric Aβ1‐42 (but not of scrambled peptide) inhibited antigen presentation by primary dendritic cells, in a dose‐dependent manner. Finally, we found that human oligomeric Aβ 1‐42 alters the transcription of key immune mediators in dendritic cells, including cytokines, chemokines and adhesion molecules.ConclusionsOur results suggest that, beyond their well‐characterised neurotoxic effects, oligomeric forms of Aβ 1‐42 exert hitherto unknown immunomodulatory properties. By inhibiting antigen presentation by cerebral APCs, Aβ 1‐42 might interfere with physiological brain immune surveillance, thus facilitating Aβ 1‐42 and tau spreading in AD.