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Published on: June 26, 2018
Ganglioside sialylation modulates tau internalization and pathology spread.
Shiying Li1,2, Yuanyuan Chen1, Tianling Song1
1Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China.
Reducing ganglioside sialylation, specifically decreasing GD1a levels, inhibits tau aggregate uptake and halts the spread of Alzheimer's disease (AD) pathology. This suggests targeting ganglioside modifications as a novel therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Gangliosides, particularly their sialylation, are crucial for cellular recognition and endocytosis.
- Proteopathic tau aggregate internalization drives Alzheimer's disease (AD) pathology propagation.
- The specific role of ganglioside sialylation in tau uptake and AD pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of mammalian sialidases (Neu1-Neu4) in modulating tau aggregation.
- To elucidate the influence of ganglioside sialylation on proteopathic tau aggregate internalization.
- To explore potential therapeutic strategies targeting ganglioside metabolism in AD.
Main Methods:
- Utilized cellular models to study tau aggregation and sialidase activity.
- Employed mouse models overexpressing Neu3 or administered GM1 to assess tau pathology spread.
- Conducted in vitro binding assays to compare GD1a and GM1 avidity for tau filaments.
- Investigated the involvement of low-density lipoprotein receptor-related protein 1 (LRP1) in tau uptake.
Main Results:
- Neu3 significantly inhibited tau aggregation induced by AD patient-derived proteopathic tau (AD P-tau).
- Overexpression of Neu3 or administration of GM1 reduced the GD1a/GM1 ratio, blocked tau pathology spread, and improved recognition in AD P-tau mice.
- GD1a enhanced tau aggregate uptake, correlating positively with internalized tau levels, while Neu3 and GM1 reduced uptake.
- GD1a facilitated LRP1-mediated tau internalization, showing higher binding avidity for tau filaments than GM1.
Conclusions:
- GD1a directly binds to tau aggregates via its sialic acid moiety, promoting LRP1-mediated neuronal uptake.
- Neu3-mediated reduction of GD1a and subsequent increase in GM1 levels inhibit tau internalization and pathology spread.
- Reducing ganglioside sialylation represents a novel therapeutic avenue for mitigating tau pathology in Alzheimer's disease.
