Abstract

Microglial cells in the brains of Alzheimer's patients are known to be recruited to amyloid-beta (Aβ) plaques where they exhibit an activated phenotype, but are defective for plaque removal by phagocytosis. In this study, we show that microglia stressed by exposure to sodium arsenite or Aβ(1–42) peptides or fibrils form ex- tensive stress granules (SGs) to which the tyrosine kinase, SYK, is recruited. SYK enhances the formation of SGs, is active within the resulting SGs and stimulates the production of reactive oxygen and nitrogen species that are toxic to neuronal cells. This sequestration of SYK inhibits the ability of microglial cells to phagocytose Escherichia coli or Aβ fibrils. We find that aged microglial cells are more susceptible to the formation of SGs; and SGs containing SYK and phosphotyrosine are prevalent in the brains of patients with severe Alzheimer's dis- ease. Phagocytic activity can be restored to stressed microglial cells by treatment with IgG, suggesting a mecha- nism to explain the therapeutic efficacy of intravenous IgG. These studies describe a mechanism by which stress, including exposure to Aβ, compromises the function of microglial cells in Alzheimer's disease and suggest ap- proaches to restore activity to dysfunctional microglial cells.

Comments

This is the publishers version of Ghosh, Soumitra & Geahlen, Robert. (2015). Stress Granules Modulate SYK to Cause Microglial Cell Dysfunction in Alzheimer's Disease. EBioMedicine. 2. 10.1016/j.ebiom.2015.09.053.

Keywords

Alzheimer's disease, microglial cells, stress granules, SYK tyrosine kinase, neurodegenerative disease, Amyloid-beta

Date of this Version

10-5-2015

DOI

10.1016/j.ebiom.2015.09.053

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