β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity

• DOI: 10.1101/2025.02.20.637701
• Publication Date: 2025-02-25T22:10:51Z
• Authors: Brandon B. Holmes; Thaddeus K. Weigel; Jesseca M. Chung; Sarah K. Kaufman; Brandon I. Apresa; James R. Byrnes; Kaan S. Kumru; Jaime Vaquer-Alicea; Ankit Gupta; Indigo V. L. Rose; Yun Zhang; Alissa L. Nana; Dina Alter; Lea T. Grinberg; Salvatore Spina; Kevin K. Leung; Carlo Condello; Martin Kampmann; William W. Seeley; Jaeda C. Coutinho...; James A. Wells
• Keywords: Apolipoprotein E; Amyloid (mycology); Pathogenesis

To elucidate the impact of Aβ pathology on microglia in Alzheimer's disease pathogenesis, we profiled surfaceome following treatment with fibrils. Our findings reveal that Aβ-associated human upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). In Drosophila amyloidosis model, glial GPC4 expression exacerbates motor deficits and reduces lifespan, indicating contributes to toxic cellular program during neurodegeneration. cell culture, enhances phagocytosis tau aggregates, shed can act trans facilitate aggregate uptake seeding neurons. Additionally, our data demonstrate GPC4-mediated effects are amplified presence APOE. These studies offer mechanistic framework linking through microglial HSPGs