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Astrocyte-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 (APOE4), the highest genetic risk factor for late-onset AD, has been shown to exacerbate tau hyperphosphorylation in mouse models. Howeve...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9407658/ https://www.ncbi.nlm.nih.gov/pubmed/35969759 http://dx.doi.org/10.1073/pnas.2108870119 |
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author | Saroja, Sivaprakasam R. Gorbachev, Kirill TCW, Julia Goate, Alison M. Pereira, Ana C. |
author_facet | Saroja, Sivaprakasam R. Gorbachev, Kirill TCW, Julia Goate, Alison M. Pereira, Ana C. |
author_sort | Saroja, Sivaprakasam R. |
collection | PubMed |
description | Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer’s disease (AD). Apolipoprotein E4 (APOE4), 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. Furthermore, the astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9-mediated activation of GPC-4 in a tauopathy mouse model robustly induced tau hyperphosphorylation. In the absence of GPC4, APOE4-induced tau hyperphosphorylation was largely diminished using in vitro tau fluorescence resonance energy transfer-biosensor cells, in human-induced pluripotent stem cell-derived astrocytes and in an in vivo mouse model. We further show that APOE4-mediated surface trafficking of APOE receptor low-density lipoprotein receptor-related protein 1 through GPC-4 can be a gateway to tau spreading. Collectively, these data support that APOE4-induced tau hyperphosphorylation is directly mediated by GPC-4. |
format | Online Article Text |
id | pubmed-9407658 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-94076582023-02-15 Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation Saroja, Sivaprakasam R. Gorbachev, Kirill TCW, Julia Goate, Alison M. Pereira, Ana C. Proc Natl Acad Sci U S A Biological Sciences Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer’s disease (AD). Apolipoprotein E4 (APOE4), 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. Furthermore, the astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9-mediated activation of GPC-4 in a tauopathy mouse model robustly induced tau hyperphosphorylation. In the absence of GPC4, APOE4-induced tau hyperphosphorylation was largely diminished using in vitro tau fluorescence resonance energy transfer-biosensor cells, in human-induced pluripotent stem cell-derived astrocytes and in an in vivo mouse model. We further show that APOE4-mediated surface trafficking of APOE receptor low-density lipoprotein receptor-related protein 1 through GPC-4 can be a gateway to tau spreading. Collectively, these data support that APOE4-induced tau hyperphosphorylation is directly mediated by GPC-4. National Academy of Sciences 2022-08-15 2022-08-23 /pmc/articles/PMC9407658/ /pubmed/35969759 http://dx.doi.org/10.1073/pnas.2108870119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Saroja, Sivaprakasam R. Gorbachev, Kirill TCW, Julia Goate, Alison M. Pereira, Ana C. Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation |
title | Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation |
title_full | Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation |
title_fullStr | Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation |
title_full_unstemmed | Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation |
title_short | Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation |
title_sort | astrocyte-secreted glypican-4 drives apoe4-dependent tau hyperphosphorylation |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9407658/ https://www.ncbi.nlm.nih.gov/pubmed/35969759 http://dx.doi.org/10.1073/pnas.2108870119 |
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