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Updated: Jun 8, 2025
07:18
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
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Arc mediates intercellular tau transmission via extracellular vesicles.
Mitali Tyagi1, Radhika Chadha1, Eric de Hoog1
1Department of Neurobiology, University of Utah, Salt Lake City, USA.
Biorxiv : the Preprint Server for Biology
|November 1, 2024
Summary
The neuronal gene Arc packages tau protein into extracellular vesicles (EVs), crucial for its cell-to-cell spread in neurodegenerative diseases like Alzheimer's. Arc deficiency halts tau transmission and protects against neuron loss.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Misfolded tau protein forms neurofibrillary tangles, driving neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia (FTD).
- Tau pathology spreads between cells, but the mechanisms of tau release and intercellular transmission are not fully understood.
- Tau can be released as free protein or within extracellular vesicles (EVs), with unclear roles in disease progression.
Purpose of the Study:
- To investigate the role of the neuronal gene Arc in tau release and intercellular transmission.
- To determine if Arc influences tau packaging into EVs and its pathological consequences.
Main Methods:
- Utilized human tau (hTau) transgenic mice (rTg4510) and Arc knock-out (Arc KO) models.
- Purified extracellular vesicles (EVs) from mouse brains for analysis of hTau content and seeding potential.
- Investigated the interaction between Arc and hTau using biochemical and imaging techniques.
- Assessed neurodegeneration and intercellular tau transmission in Arc KO mice.
Main Results:
- Arc is critical for packaging tau into EVs; Arc KO mice showed significantly reduced hTau in EVs and impaired seeding ability.
- Arc facilitates hTau release in EVs via the I-BAR protein IRSp53, but not free tau release.
- Arc directly binds hTau, forming a complex found in both mouse and human brain tissue.
- Pathological intracellular hTau accumulated in Arc KO mice, correlating with accelerated hippocampal neuron loss.
- Intercellular tau transmission was significantly abrogated in Arc KO mice.
Conclusions:
- Arc-dependent release of tau via EVs is a key mechanism for intracellular tau elimination.
- Arc plays a significant role in intercellular tau transmission, impacting neurodegenerative disease progression.
- Targeting Arc-mediated EV release could be a therapeutic strategy for tauopathies.
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