Tracking tau and cellular responses in human iPSC-microglia: from uptake to seedable secretion, including in
Maria Kreger Karabova1, Anna Del Ser-Badia1, Anne Hedegaard1
1James and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Introduction:
Microglia have been implicated in the templated spread of tau aggregates in tauopathies through mouse studies. However, it is unclear whether these findings translate to human disease.
Methods:
We challenged human induced pluripotent stem cell (iPSC)-derived microglia-like-cells (iMGL) with monomeric and fibrillar recombinant tau and tau purified from Alzheimer's patient brains, examining in detail the uptake, processing, release, and seeding of tau by microglia.
Results:
iMGL take up tau via lipoprotein receptor-related protein 1 (LRP)1 and heparan sulfate proteoglycans, with leucine-rich repeat kinase 2 affecting LRP1 trafficking. Monomeric tau is digested effectively with minimal effects on iMGL, but recombinant or brain-derived tau fibrils induce chemokine/interferon response subtypes, alongside downregulation of homeostatic genes. Fibrillar tau is degradation-resistant, can escape into the cytoplasm, and becomes phosphorylated on two specific residues. iMGL release partially digested fibrillar tau, including in extracellular vesicles, visualized by cryo-electron microscopy, that seed aggregation in neurons.
Discussion:
Our study reveals new insights into human microglial responses to tau, highlighting opportunities to limit pathogenic tau spread.
Insights
Human microglia uptake and process tau aggregates, a key feature of tauopathies. Fibrillar tau resists digestion, is released by microglia, and seeds neuronal tau aggregation, offering therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are implicated in tau aggregate spread in tauopathies via mouse studies.
- Translational relevance of microglial function in human tauopathies remains unclear.
Purpose of the Study:
- Investigate human microglia-like cells' (iMGL) response to monomeric and fibrillar tau.
- Elucidate mechanisms of tau uptake, processing, release, and seeding by human microglia.
Main Methods:
- Utilized human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL).
- Challenged iMGL with recombinant and patient-derived tau species.
- Analyzed tau uptake, intracellular processing, release, and seeding potential using various techniques including cryo-electron microscopy.
Main Results:
- iMGL internalize tau via LRP1 and heparan sulfate proteoglycans.
- Fibrillar tau induces inflammatory responses and resists digestion, leading to phosphorylation and cytoplasmic escape.
- iMGL release seeding-competent tau aggregates within extracellular vesicles.
Conclusions:
- Human microglia actively respond to and process pathogenic tau aggregates.
- Fibrillar tau triggers specific microglial responses and can be spread via extracellular vesicles.
- Findings highlight microglial pathways as potential targets for limiting tauopathy progression.
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