INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia

Terzioglu, G.; Karp, E. S.; Heuer, S. E.; Haage, V. C.; De Jager, P. L.; Young-Pearse, T. L.

doi:10.1101/2025.10.27.684632

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bioRxiv · 10.1101/2025.10.27.684632

INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia

Terzioglu, G.·Karp, E. S.·Heuer, S. E.·Haage, V. C.·De Jager, P. L.·Young-Pearse, T. L.

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Abstract

INPP5D, which encodes SHIP1, is genetically associated with Alzheimers disease (AD) risk and regulates microglial immune function. Here we identified SHIP1 as a regulator of endo-lysosomal homeostasis in human microglia. INPP5D haploinsufficiency impaired endosome maturation and lysosomal degradation, leading to lipid droplet accumulation, lysosomal stress, and NLRP3 inflammasome activation. SHIP1-deficient microglia shifted from an immune-responsive state toward a disease-associated state with elevated cargo-selective phagocytosis. Although amyloid-{beta} uptake was unaffected, SHIP1-deficient microglia accumulated intracellular amyloid-{beta} and exhibited exacerbated lipid droplet accumulation, consistent with defective lysosomal processing. Proteomic analysis of genetically diverse human microglia revealed that the protective INPP5D rs10933431 variant is associated with elevated phosphatase-domain containing SHIP1, and protein profiles consistent with enhanced endolysosomal trafficking. In mice xenografted with SHIP1-deficient human microglia, high amyloid-{beta} burden exacerbated lysosomal, lipid droplet and inflammasome phenotypes. Together, these findings identify disrupted endo-lysosomal trafficking and degradative capacity as mechanisms linking INPP5D dysfunction to disease-associated microglial states in AD.

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Terzioglu, G., Karp, E. S., Heuer, S. E., Haage, V. C., De Jager, P. L., Young-Pearse, T. L.. 2025-10-27. INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia. https://doi.org/10.1101/2025.10.27.684632

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