Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation
Open accessAbstract
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.
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Astrocyte-secreted ApoE4 and glypican-4 bind to LRP1 in neurons, leading to tau accumulation and propagation.
“Saroja et al. demonstrated that astrocyte-secreted ApoE4 and glypican-4 (GPC-4) bind to LRP1 in neurons, leading to tau accumulation and propagation [141] (Fig. 1).”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [141]
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- Authors
- Saroja, S. R., Gorbachev, K., Julia, T., Goate, A. M., & Pereira, A. C.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Corresponding author
- Pereira, Ana C.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2022-08-15
- Volume
- 119
- Issue
- 34
- Pages
- e2108870119-e2108870119
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC9407658
- OpenAlex
- W4291910168
- Cited by
- 75
- References
- 68
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 23 · 2023: 12 · 2022: 2
- FWCI
- 9.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (K01AG062683, U01AG058635, R01AG064020, U19AG069701)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- GPC4, APOE ε4, tau hyperphosphorylation, Alzheimer's disease, astrocytes, apoE receptors, LDL receptor, tau propagation, protein-protein interaction, tauopathy
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Disease Models, Animal, Humans, Mice, Transgenic, Phosphorylation, tau Proteins, Tauopathies, Mice, Apolipoprotein E4, Apolipoprotein E2, Glypicans
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