Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds
Open accessAbstract
Significance: Prion-like propagation of proteopathic seeds may underlie the progression of neurodegenerative diseases, including the tauopathies and synucleinopathies. Aggregate entry into the cell is a crucial step in transcellular propagation. We used chemical, enzymatic, and genetic methods to identify heparan sulfate proteoglycans as critical mediators of tau aggregate binding and uptake, and subsequent seeding of normal intracellular tau. This pathway mediates aggregate uptake in cultured cells, primary neurons, and brain. α-Synuclein fibrils use the same entry mechanism to seed intracellular aggregation, whereas huntingtin fibrils do not. This establishes the molecular basis for a key step in aggregate propagation.
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Tau aggregation is promoted by proteoglycans, which are present in tangles, and are involved in the prion-like spread of tau pathology.
“Tau aggregation is promoted by proteoglycans [186], which are present in tangles, and are involved in the prion-like spread of tau pathology [187].”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [187]
The Discussion (page not given) identifies heparan sulfate proteoglycans as mediators of tau-aggregate uptake and cell-to-cell propagation, supporting their role in prion-like spread. Our copy does not establish the other point attributed to this citation: that proteoglycans are present in tangles. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCell surface HSPGs mediate a large portion of neuronal uptake of Tau monomers and aggregates.
“Recent findings show that cell surface HSPGs mediate a large portion of neuronal uptake of Tau monomers and aggregates46,57.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [57]
The Discussion reports that HSPGs mediate tau aggregate uptake into neurons in vitro and in vivo. The Results distinguish fibrils from monomers, stating that tau repeat-domain fibrils, but not monomers, are readily internalized into neural precursor cells. This source therefore supports the aggregate portion of the claim, but not HSPG-mediated neuronal uptake of tau monomers. (LLM, conf=0.90)
Experimental — accuracy not yet measuredHSPGs are largely responsible for neuronal Tau uptake.
“Previous work showed that HSPGs are largely responsible for neuronal Tau uptake46–48,57.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [57]
The Discussion says HSPGs mediate binding and internalization of tau aggregates into neurons, and the primary-neuron experiment reports a 43% reduction in full-length tau fibril uptake after Ext1 knockdown. The source supports a major role for HSPGs in neuronal uptake of aggregated tau, but does not establish that they are largely responsible for uptake of Tau in general. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHSPGs are responsible for neuronal uptake of tau and the R136S mutation causes impaired binding affinity of APOE to HSPGs, leading to reduced tau pathology.
“HSPGs are responsible for neuronal uptake of tau and the R136S mutation causes impaired binding affinity of APOE to HSPGs, leading to reduced tau pathology [15, 41, 76, 84, 85].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [85]
The Discussion (page unavailable) reports that HSPGs mediate uptake of tau aggregates into primary hippocampal neurons, supporting the first part of the sentence. The copy does not address the APOE R136S mutation, its binding affinity for HSPGs, or a resulting reduction in tau pathology (searched: R136S and APOE). (LLM, conf=0.90)
Experimental — accuracy not yet measuredNeuronal uptake of exogenous Tau in culture can be competitively inhibited with the addition of heparin.
“Additionally, neuronal uptake of exogenous Tau in culture can be competitively inhibited with the addition of heparin46,57.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [57]
Biochemical analysis showed a vastly reduced affinity of the APOE3-Christchurch variant to heparin.
“Biochemical analysis showed a vastly reduced affinity of this apoE variant to heparin which has been implicated in multiple Aβ- and tau-related pathogenic pathways (34, 35).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [34]
Heparin sulfate has been implicated in cell-to-cell spread of tau and other AD-associated processes.
“Heparin sulfate has been implicated in cell-to-cell spread of tau [45] as well as other AD-associated processes [46], pointing to potential importance of this pathway for dominant AD.”
From Genetic associations with age at dementia onset in the <i>PSEN1 E280A</i> Colombian kindred (2023) · cites this paper as [45]
Previous work has implicated HSPGs as a potential receptor for tau internalization.
“Previous work has implicated HSPGs as a potential receptor for tau internalization14,16.”
From Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs) (2018) · cites this paper as [16]
Tau internalization has been linked to heparan sulfate proteoglycans previously.
“Tau internalization has also been linked to HSPGs previously16”
From Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs) (2018) · cites this paper as [16]
TFEB induces astrocytic trafficking of tau fibrils via macropinocytosis, possibly through interaction with heparan sulfate proteoglycans (HSPGs).
“TFEB induces astrocytic trafficking of tau fibrils via macropinocytosis, possibly through interaction with heparan sulfate proteoglycans (HSPGs) [200, 201].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [200]
Both αSyn and tau appear to be secreted by similar exosome-mediated release mechanisms and both proteins can be endocytosed via the heparin sulfate proteoglycans pathway.
“both αSyn and tau appear to be secreted by similar exosome-mediated release mechanisms [99, 100] and both proteins can also be endocytosed via the heparin sulfate proteoglycans (HSPGs) pathway [101].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [101]
αSyn is secreted within exosomes in a calcium-dependent manner and can be taken up by cells via HSPGs.
“Similar to tau, it has been suggested that αSyn is secreted within exosomes in a calcium-dependent manner [100]. It was further proposed that αSyn can be taken up by cells via HSPGs similar to what has been reported for tau and Aβ [101]”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [101]
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Extracellular Monomeric Tau Is Internalized by Astrocytes
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- Authors
- Holmes, B. B., DeVos, S. L., Kfoury, N., Li, M., Jacks, R., Yanamandra, K., Ouidja, M. O., Brodsky, F. M., Marasa, J., Bagchi, D. P., Kotzbauer, P. T., Miller, T. M., Papy-Garcia, D., & Diamond, M. I.
- Affiliations
- Washington University in St. Louis (US)
- University of California, Berkeley (US)
- Centre National de la Recherche Scientifique (FR)
- University of California, San Francisco (US)
- Laboratoire Croissance, Réparation et Régénération Tissulaires, Centre National de la Recherche Scientifique FRE24-12, Université Paris XII-Val de Marne, 94010 Créteil, France;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-07-29
- Volume
- 110
- Issue
- 33
- Pages
- E3138-47
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3746848
- OpenAlex
- W2089607910
- Cited by
- 859
- References
- 9
- Citations by year
- 2026: 46 · 2025: 63 · 2024: 58 · 2023: 59 · 2022: 89 · 2021: 89 · 2020: 110 · 2019: 73 · 2018: 76 · 2017: 52 · 2016: 57 · 2015: 46 · 2014: 36 · 2013: 5
- FWCI
- 33.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Cancer Institute (P50 CA94056, P50CA094056, P30CA091842)
- National Institute of General Medical Sciences (R01GM038093)
- National Institute of Neurological Disorders and Stroke (F31NS079039, P30NS057105, K08NS074194, R01NS071835)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Keywords
- heparan sulfate proteoglycans, tau fibrils, alpha-synuclein fibrils, neurodegeneration, tauopathy, synucleinopathies, EXT1, prion-like propagation, intracellular aggregation
- MeSH terms
- Actins, Amyloid, Animals, Flow Cytometry, Humans, Immunohistochemistry, Indoles, Male, Mice, Inbred C57BL, Microscopy, Fluorescence, Pinocytosis, tau Proteins, Heparan Sulfate Proteoglycans, Fluorescence Resonance Energy Transfer, Mice, HEK293 Cells, Neural Stem Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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