Mechanisms of action of naturally occurring antibodies against ß-amyloid on microglia.

BACKGROUND: Naturally occurring autoantibodies against amyloid-ß (nAbs-Aß) have been shown to exert beneficial effects on transgenic Alzheimer's disease (AD) animals in vivo and on primary neurons in vitro. Not much is known about their effect on microglial cells. Our aim was to investigate the effect of nAbs-Aß on amyloid-ß (Aß)-treated microglial cells in vitro with respect to cell viability, stress pathways, cytokine production and phagocytotic abilities and whether these effects can be conveyed to neurons. METHODS: Primary microglial cells isolated from Swiss Webster mouse mesencephalons on embryonic day 13.5 were pretreated with nAbs-Aß and then treated with Aß oligomers. After 3 hours, phagocytosis as well as western blot analysis were evaluated to measure the amount of phagocytized Aß. Cell viability was analyzed using an MTT assay 24 hours after treatment. Pro-inflammatory cytokines in the supernatants were analyzed with ELISAs and then we treated primary neuronal cells with these conditioned microglia supernatants. Twenty-four hours later we did a MTT assay of the treated neurons. We further investigated the effect of a single nAbs-Aß administration on Tg2576 mice in vivo. RESULTS: Upon co-administration of Aß and nAbs-Aß no change in microglia viability was observed. However, there was an increase in phosphorylated p38 protein level, an increase in the pro-inflammatory cytokines TNF-α and IL-6 and an increase in Aß uptake by microglial cells. Treatment of primary neurons with conditioned microglia medium led to a 10% improvement in cell viability when nAbs-Aß were co-administered compared to Aß-treated cells alone. We were unable to detect changes in cytokine production in brain lysates of Tg2576 mice. CONCLUSIONS: We provide evidence on the mechanism of action of nAbs-Aß on microglia in vitro. Interestingly, our in vivo data indicate that nAbs-Aß administration should be considered as a therapeutic strategy in AD, since there is no inflammatory reaction.