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Stress Granules Modulate SYK to Cause Microglial Cell Dysfunction in Alzheimer's Disease
Soumitra Ghosh1, Robert L Geahlen1
1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
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.
Insights
Stress causes microglial cells to form stress granules (SGs) that trap SYK, impairing Alzheimer's disease plaque removal. Restoring microglial phagocytosis offers therapeutic potential.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial cells in Alzheimer's disease (AD) are recruited to amyloid-beta (Aβ) plaques but fail to clear them via phagocytosis.
- Stressors like Aβ peptides or fibrils can compromise microglial function.
Purpose of the Study:
- To investigate the mechanism by which stress impairs microglial phagocytosis in Alzheimer's disease.
- To identify molecular players involved in stress-induced microglial dysfunction.
Main Methods:
- Exposure of microglial cells to stressors (sodium arsenite, Aβ peptides/fibrils).
- Analysis of stress granule (SG) formation and recruitment of tyrosine kinase SYK.
- Assessment of reactive oxygen and nitrogen species production.
- Measurement of phagocytic activity against E. coli and Aβ fibrils.
- Examination of microglial cells from Alzheimer's disease patients and aged mice.
Main Results:
- Stressed microglia form SGs that sequester active SYK, enhancing SG formation.
- SYK within SGs promotes toxic reactive species production and inhibits phagocytosis of Aβ and bacteria.
- Aged microglia are more prone to SG formation.
- SGs containing SYK and phosphotyrosine are abundant in severe Alzheimer's disease brains.
- Intravenous IgG treatment restores phagocytic capacity in stressed microglia.
Conclusions:
- Stress, including Aβ exposure, leads to SG formation in microglia, sequestering SYK and impairing phagocytosis.
- This mechanism contributes to microglial dysfunction in Alzheimer's disease.
- Restoring microglial phagocytic activity, potentially via mechanisms like IVIg therapy, is a promising therapeutic avenue.
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