Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex.

Abstract

Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The transmission of aggregates requires neuron-released Tau to interact with surface receptors on target cells. However, the underlying molecular mechanisms in astrocytes and downstream effects are unclear. Here, using a spatially resolved proteomic mapping strategy, we show that integrin αV/β1 receptor binds recombinant human Tau, mediating the entry of Tau fibrils in astrocytes. The binding of distinct Tau species to the astrocytic αV/β1 receptor differentially activate integrin signaling. Furthermore, Tau-mediated activation of integrin signaling results in NFκB activation, causing upregulation of pro-inflammatory cytokines and chemokines, induction of a sub-group of neurotoxic astrocytic markers, and release of neurotoxic factors. Our findings suggest that filamentous recombinant human Tau-mediated activation of integrin signaling induces astrocyte conversion towards a neurotoxic state, providing a mechanistic insight into tauopathies.

• Authors: Peng Wang, Yihong Ye
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 95 (01 04 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33398028 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Heparan Sulfate Proteoglycans
• NF-kappa B
• Receptors, Vitronectin
• Recombinant Proteins
• STAT3 Transcription Factor
• Talin
• integrin alphavbeta1
• tau Proteins
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Animals
• Astrocytes (metabolism, pathology)
• Cells, Cultured
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• HEK293 Cells
• Heparan Sulfate Proteoglycans (metabolism)
• Humans
• Inflammation (pathology)
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Neurons (metabolism, pathology)
• Protein Binding
• Receptors, Vitronectin (metabolism)
• Recombinant Proteins (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• Talin (metabolism)
• tau Proteins (metabolism, ultrastructure)
• Mice