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Our findings reveal that A\u03b2-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a\n                    <jats:italic>Drosophila<\/jats:italic>\n                    amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act\n                    <jats:italic>in trans<\/jats:italic>\n                    to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer\u2019s disease brain, microglial GPC4 expression surrounding A\u03b2 plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. 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