Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity
Open accessAbstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and has no disease-modifying treatment yet. The hallmarks of AD are two amyloidogenic proteins: tau and amyloid β (Aβ). Tau undergoes several posttranslational modifications, including N-glycosylation. Tau was reported to be N-glycosylated in AD brains, but not in healthy counterparts, which may affect AD etiology. Here, we aimed to examine the effect of N-glycosylation on aggregation propensity of tau. To that end, a novel SH-SY5Y cell-based model was generated in which recombinant human tau (htau) is forced to be secreted from the cells. Secreted htau was found to localize in the secretory pathway compartments and to undergo N-glycosylation. Following N-glycan cleavage of the secreted htau, various biophysical results collectively indicated that the untreated N-glycosylated secreted htau is markedly less aggregative, contains thinner and shorter fibrils, as compared to treated de-glycosylated secreted htau. This finding shows that N-glycans attached to htau may affect its aggregation. This could help to better understand the effect of N-glycosylated htau on AD progression.
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N-glycosylated tau is prone to phosphorylation, but shows reduced aggregation.
“Several studies suggest that N-glycosylated tau is prone to phosphorylation, but shows reduced aggregation [184, 185].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [185]
Tau undergoes both N-linked glycosylation and O-linked N-acetylglucosaminylation (O-GlcNAcylation), which have been proposed to affect tau phosphorylation and aggregation.
“In addition, tau also undergoes both N-linked glycosylation (N-glycosylation) [171] and O-linked N-acetylglucosaminylation (O-GlcNAcylation) [172], which have been proposed to affect tau phosphorylation and aggregation [173].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [173]
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References 41 · Cited by 50
- Authors
- Losev, Y., Paul, A., Frenkel-Pinter, M., Abu-Hussein, M., Khalaila, I., Gazit, E., & Segal, D.
- Affiliations
- Tel Aviv University (IL)
- Ben-Gurion University of the Negev (IL)
- Corresponding author
- Segal, Daniel
- Venue
- Scientific Reports
- Published
- 2019-02-19
- Volume
- 9
- Issue
- 1
- Pages
- 2254-2254
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6381127
- OpenAlex
- W2915570570
- Cited by
- 50
- References
- 41
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 4
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Rosetrees Trust (M238-F1)
- Tel Aviv University
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, N-glycosylation, Alzheimer's disease, protein aggregation, SH-SY5Y cells, fibril morphology, post-translational modification, amyloidosis
- MeSH terms
- Alzheimer Disease, Glycosylation, Humans, Models, Biological, Protein Processing, Post-Translational, tau Proteins, Cell Line, Tumor, Protein Aggregation, Pathological
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