Lykhmus_2016_Immunobiology_221_1355

Nicotinic acetylcholine receptors of alpha7 subtype (alpha7 nAChRs) attenuate the inflammatory cytokines production by macrophages and are involved in pathogenesis of Alzheimer disease by directly influencing the processing of amyloid-beta (Abeta) precursor protein in the brain. Previously we found that regular injections of bacterial lipopolysaccharide (LPS) decreased the level of alpha7 nAChRs and stimulated accumulation of Abeta peptide (1-42) in the brain of mice resulting in memory impairment. Similar effects were observed in mice immunized with recombinant extracellular domain (1-208) of alpha7 nAChR subunit. However, the mechanism of inflammation-like effect of alpha7-specific antibodies remained unclear. The aim of the present study was to reveal the impact of carbohydrate component of recombinant alpha7(1-208) produced in yeast in the functional effect of resulting antibodies. For this purpose, C57Bl/6 mice were immunized with either initial alpha7(1-208) or with that pre-treated with endoglycosidase. Control groups of mice obtained injections of either LPS or complete Freund's adjuvant. Mice were tested for memory performance, their blood sera were examined for the presence and fine specificity of alpha7(1-208)-specific antibodies and the brain preparations were studied for the levels of alpha7 nAChR, Abeta(1-42) and interleukin-6. It was found that the original alpha7(1-208) was more immunogenic than the deglycosylated one, and their epitopes were recognized with different efficiency. In contrast to LPS and original alpha7(1-208), deglycosylated alpha7(1-208) did not stimulate interleukin-6 elevation in the brain, i.e. had no pro-inflammatory effect. Nevertheless, immunizations with either the original or deglycosylated alpha7(1-208) resulted in similar decrease of alpha7 nAChRs, accumulation of Abeta(1-42) in the brain and significant episodic memory decline, comparable to those exerted by LPS injections. We conclude that the decrease of alpha7 nAChR density, caused by alpha7(1-208)-specific antibody, is critical for Abeta(1-42) accumulation and episodic memory impairment, while pro-inflammatory capacity of alpha7(1-208)-specific antibody plays a secondary role for the development of Alzheimer-like symptoms.