The single greatest risk factor for neurodegenerative diseases is aging. Aging of cells such as microglia in the nervous system has an impact not only on the ability of those cells to function but also on cells they interact with. We have developed a model microglia system that recapitulates the dystrophic/senescent phenotype, and we have combined this with the study of β-amyloid processing. The model is based on the observation that aged microglia have increased iron content. By overloading a human microglial cell line with iron, we were able to change the secretory profile of the microglia. When combining these senescent microglia with SH-SY5Y cells, we noted an increase in extracellular β-amyloid. The increased levels of β-amyloid were due to a decrease in the release of insulin-degrading enzyme by the model senescent microglia. Further analysis revealed that the senescent microglia showed both decreased autophagy and increased ER stress. These studies demonstrate the potential impact of an aging microglial population in terms of β-amyloid produced by neurons, which could play a causal role in diseases like Alzheimer's disease. Our results also further develop the potential utility of an in vitro model of senescent microglia for the study of brain aging and neurodegenerative disease.
Keywords: APP; ER stress; autophagy; insulin degrading enzyme; microglia; β-amyloid.