biostudies-literatureSaroja SRHHS | National Institutes of HealthNIA NIH HHSe2108870119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9407658biostudies-literatureUnknown119(34)Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer's disease (AD). Apolipoprotein E4 (<i>APOE4</i>), the highest genetic risk factor for late-onset AD, has been shown to exacerbate tau hyperphosphorylation in mouse models. However, the exact mechanisms through which APOE4 induces tau hyperphosphorylation remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), which we identify as a binding partner of APOE4, drives tau hyperphosphorylation. We discovered that first, GPC-4 preferentially interacts with APOE4 in comparison to APOE2, considered to be a protective allele to AD, and second, that postmortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. FurthermoProceedings of the National Academy of Sciences of the United States of AmericaAstrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation.PMC9407658K76 AG054772R01 AG063819U19 AG069701U01AG058635U19AG069701R01 AG064020K01 AG062683K01AG062683R01AG064020U01 AG058635Saroja SRJulia TGoate AMPereira ACGorbachev KfalseAstrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation.Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer's disease (AD). Apolipoprotein E4 (<i>APOE4</i>), the highest genetic risk factor for late-onset AD, has been shown to exacerbate tau hyperphosphorylation in mouse models. However, the exact mechanisms through which APOE4 induces tau hyperphosphorylation remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), which we identify as a binding partner of APOE4, drives tau hyperphosphorylation. We discovered that first, GPC-4 preferentially interacts with APOE4 in comparison to APOE2, considered to be a protective allele to AD, and second, that postmortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. Furthermo2022-01-01T00:00:00Z2022 Aug2026-06-04T04:57:08.448Z2025-04-19T13:28:21.104ZS-EPMC94076583596975910.1073/pnas.2108870119