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

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 alpha V/beta 1 receptor binds recombinant human Tau, mediating the entry of Tau fibrils in astrocytes. The binding of distinct Tau species to the astrocytic alpha V/beta 1 receptor differentially activate integrin signaling. Furthermore, Tau-mediated activation of integrin signaling results in NF kappa B 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. The mechanisms underlying the transmission of Tau in astrocytes are unclear. Here, the authors show that the entry of filamentous recombinant human Tau into astrocytes via the integrin alpha V/ beta 1 complex stimulates integrin signaling, resulting in activation of NF kappa B and astrocyte conversion towards a neurotoxic state.

Automated summary

Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The entry of filamentous recombinant human Tau into astrocytes via the integrin alpha V/beta 1 complex stimulates integrin signaling, resulting in activation of NF kappa B and astrocyte conversion towards a neurotoxic state.