Altered Processing of β-Amyloid in SH-SY5Y Cells Induced by Model Senescent Microglia

Abstract

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.

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

“…We showed that this change in the microglia was a result of decreased autophagy-related release of IDE. This verified that causing an aged-related change in model microglia could induce an AD-related change, increased levels of b-amyloid (Angelova and Brown 2018a).…”

“…Lastly, we looked at cellular processes that are linked to altered cellular function, namely autophagy and ER stress. By monitoring proteins associated with both processes such mammalian target of rapamycin and eukaryotic translation initiation factor 2A, we were able to demonstrate that our model aged microglia showed increased ER stress and decreased autophagy (Angelova and Brown ). Altogether, the changes we observed in our iron‐overload based model of aging microglia were similar to both senescence and dystrophic alteration (Fig.…”

“…We used both primary mouse microglia and human and mouse microglia cell lines and exposed them to high iron concentrations. These different microglia all showed significant retention of the iron along with changes in morphology, cytokines, and ROS (Angelova and Brown ; Angelova and Brown ). This suggests the adoption of an altered secretory profile similar to SASP.…”

“…However, as mentioned, it remains unclear as to whether loss of proliferative ability is a valid indicator of senescent/dystrophic phenotype for a cell type that is meant to be able to divide as part of its normal activities. Changes in other markers of both aging and senescence were also observed such as altered expression of the proteins SIRT-1, Kv.1.3, and altered glutamate release (Angelova and Brown 2018a;Angelova and Brown 2018b). Lastly, we looked at cellular processes that are linked to altered cellular function, namely autophagy and ER stress.…”

“…Such evidence requires the ability to specifically identify and target these cells. To this end, there have been recent attempts to create in vitro models of senescent microglia and verify that they induce changes in neurons that reflect changes seen in neurodegenerative diseases (Angelova and Brown ; Angelova and Brown ). This review will present the evidence that such new models of senescent microglia are paving the way to their in vivo identification and a fuller elucidation of their role in brain aging and disease.…”