{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Saroja SR"],"funding":["HHS | National Institutes of Health","NIA NIH HHS"],"pagination":["e2108870119"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9407658"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["119(34)"],"pubmed_abstract":["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. Furthermo"],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation."],"pmcid":["PMC9407658"],"funding_grant_id":["K76 AG054772","R01 AG063819","U19 AG069701","U01AG058635","U19AG069701","R01 AG064020","K01 AG062683","K01AG062683","R01AG064020","U01 AG058635"],"pubmed_authors":["Saroja SR","Julia T","Goate AM","Pereira AC","Gorbachev K"],"additional_accession":[]},"is_claimable":false,"name":"Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation.","description":"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. Furthermo","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Aug","modification":"2026-06-04T04:57:08.448Z","creation":"2025-04-19T13:28:21.104Z"},"accession":"S-EPMC9407658","cross_references":{"pubmed":["35969759"],"doi":["10.1073/pnas.2108870119"]}}