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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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Extracellular tau clearance is governed by its aggregation state and independent of microglial activation by LPS and

Andrew Shultz1, Anna Vincze2, Todd T Yau2

  • 1Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Amherst, MA, USA; Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Amherst, MA, USA.

Neurobiology of Disease
|August 20, 2025
PubMed

Insights

Human microglia clear tau protein via their endo-lysosome system, a process independent of acute inflammatory activation. This finding offers new insights into regulating tau pathology in neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Immunology

Background:

  • Microglia, the brain's resident immune cells, play a critical role in neuroinflammation and disease.
  • The precise mechanisms by which microglia interact with and clear extracellular tau, a key protein implicated in Alzheimer's disease and other tauopathies, are not fully understood.

Purpose of the Study:

  • To investigate the cellular mechanisms and kinetics of extracellular tau processing by human induced pluripotent stem cell (iPSC)-derived microglia.
  • To determine the impact of microglial inflammatory activation on tau internalization and clearance.

Main Methods:

  • Development of a quantitative platform for analyzing tau processing in iPSC-derived microglia.
  • Characterization of tau internalization and clearance using both monomeric and fibrillar tau species.
  • Assessment of the effects of acute inflammatory stimulation on microglial tau uptake and degradation.

Main Results:

  • iPSC-derived microglia internalize monomeric and fibrillar tau via distinct cellular pathways.
  • The rate of tau clearance by microglia differs depending on the tau species.
  • While acute inflammatory activation modifies tau endocytosis in microglia, it does not significantly alter tau clearance rates.
  • The microglial endo-lysosome system is identified as a key regulator of tau pathology, operating independently of acute inflammatory responses.

Conclusions:

  • The endo-lysosome pathway in microglia is a critical determinant of tau pathology progression.
  • Microglial tau clearance is decoupled from acute inflammatory activation, suggesting distinct regulatory mechanisms.
  • These findings provide a novel perspective on targeting microglial function to manage tauopathies.
Keywords:
Endo-lysosomal dysfunctionInflammationLRP1MicrogliaTauTau spread

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