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Updated: Jun 4, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms
Kristian F Falkon1,2, Liliana Danford2, Eduardo Gutierrez Kuri1,2
1Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA.
Introduction:
Alzheimer's disease (AD) and other tauopathies are characterized by intracellular aggregates of microtubule-associated protein tau that are actively released and promote proteopathic spread. Microglia engulf pathological proteins, but how they endocytose tau is unknown.
Methods:
We measured endocytosis of different tau species by microglia after pharmacological modulation of macropinocytosis or clathrin-mediated endocytosis (CME) or antagonism/genetic depletion of known tau receptors heparan-sulfate proteoglycans (HSPGs) and low-density lipoprotein receptor-related protein 1 (LRP1).
Results:
Dynamin inhibition decreased microglial endocytosis of all tested tau species. Meanwhile, HSPG antagonism blocked only fibril uptake, and LRP1 antagonism or genetic depletion inconsistently inhibited the endocytosis of fibrils and monomers. Cre recombinase robustly enhanced tau uptake with partial selectivity for fibrils.
Discussion:
These data show that microglia take up both tau monomers and aggregates via a dynamin-dependent form of endocytosis (eg, CME) but may differ in using HSPGs for entry depending on species.
Highlights:
Microglial endocytosis of tau monomers and fibrils is dynamin-dependent. HSPG antagonism blocks microglial uptake of tau fibrils but not monomers. LRP1 antagonism or knockdown inconsistently inhibits tau uptake. TAT-Cre stimulates semi-selective uptake of fibrils over monomers.
Insights
Microglia engulf tau proteins via dynamin-dependent endocytosis, potentially using heparan sulfate proteoglycans for fibril uptake. This research clarifies how microglia internalize tau in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) and tauopathies involve extracellular tau aggregates that spread pathology.
- Microglia, the brain's immune cells, engulf pathological proteins, but their mechanisms for tau endocytosis remain unclear.
Purpose of the Study:
- To investigate the mechanisms by which microglia endocytose different species of tau.
- To identify the specific cellular pathways and receptors involved in microglial tau uptake.
Main Methods:
- Assessed microglial endocytosis of tau monomers and fibrils.
- Pharmacologically modulated macropinocytosis and clathrin-mediated endocytosis (CME).
- Investigated the role of heparan-sulfate proteoglycans (HSPGs) and low-density lipoprotein receptor-related protein 1 (LRP1) using antagonism and genetic depletion.
Main Results:
- Dynamin inhibition reduced the endocytosis of all tested tau species by microglia.
- Heparan-sulfate proteoglycan (HSPG) antagonism specifically blocked fibril uptake, not monomer uptake.
- Low-density lipoprotein receptor-related protein 1 (LRP1) antagonism or depletion showed inconsistent effects on tau endocytosis.
- Cre recombinase treatment enhanced tau uptake, with a preference for fibrils over monomers.
Conclusions:
- Microglial uptake of tau monomers and fibrils is dependent on dynamin, suggesting a role for pathways like CME.
- Heparan-sulfate proteoglycans (HSPGs) are involved in the uptake of tau fibrils but not necessarily monomers.
- The precise roles of LRP1 and other receptors in microglial tau endocytosis require further investigation.
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