title: Stress Granules Modulate SYK to Cause Microglial Cell Dysfunction in Alzheimer's Disease.
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 extensive 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 disease. Phagocytic activity can be restored to stressed microglial cells by treatment with IgG, suggesting a mechanism 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 approaches to restore activity to dysfunctional microglial cells.
authors: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
authors: Soumitra
authors: S
authors: Ghosh
authors: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
authors: Robert L
authors: RL
authors: Geahlen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species; D013312:Stress, Physiological; D000072377:Syk Kinase
chemical_list: D016229:Amyloid beta-Peptides; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase
keywords: AD, Alzheimer's disease; Alzheimer's disease; Amyloid-beta; Aβ, amyloid-beta; IgG, immunoglobulin G; MG, microglial cells; Microglial cells; Neurodegenerative disease; SYK tyrosine kinase; Stress granules