September 29, 2021

Understanding the role of SHIP1 in Alzheimer’s Disease using iPSC-derived Microglia-like cells (iMGLs)

Vicky Chou, BA

Additional Authors: Seeley B Fancher, Richard V Pearse, Tracy L Young-Pearse

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects memory and other cognitive functions. Recent studies suggest that the resident immune cells of the brain, microglia, may play an active role in neurodegeneration either by engulfing synapses or secreting pro-inflammatory cytokines in response to elevated Aß and dysregulated tau. Thus, understanding the regulation of microglial activation is critical towards illuminating the role of microglia in the adult human brain and in the disease state. SHIP1, or SH2-domain containing inositol polyphosphate 5-phosphatase 1, is a protein that has been identified in GWAS studies to be associated with late-onset forms of Alzheimer’s disease. In peripheral immune cells, SHIP1 has been shown to dephosphorylate phosphatidylinositol‐3,4,5‐trisphosphate [PI(3,4,5)P3] to generate phosphatidylinositol‐3,4‐bisphosphate [PI(3,4)P2] and regulate AKT signaling. However, the function of SHIP1 is largely unknown in the brain. By immunostaining for SHIP1 in post-mortem human brain tissue, we have demonstrated that SHIP1 expression is restricted to microglia. By inhibiting SHIP1 in iPSC-derived microglia-like cells in culture, we have found that there is an increase in IL-1ß and IL-18 secretion, implicating SHIP1 in inflammasome regulation. Inflammasome involvement was confirmed by interrogating various steps of inflammasome activation through inflammasome inhibitors and immunostaining for inflammasome formation. Ongoing work involves unbiased characterization of changes in the proteosome in models of acute or chronic loss of SHIP1 function to be able to better to further define the connection between SHIP1 and inflammasome signaling. Together, this work shows that SHIP1 expression regulates inflammasome activation in human microglia.

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