Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies
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RESEARCH
Open Access
Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies Meryem Tardivel1, Séverine Bégard1†, Luc Bousset2†, Simon Dujardin1,3†, Audrey Coens2, Ronald Melki2, Luc Buée1,4*† and Morvane Colin1,4*†
Abstract A given cell makes exchanges with its neighbors through a variety of means ranging from diffusible factors to vesicles. Cells use also tunneling nanotubes (TNTs), filamentous-actin-containing membranous structures that bridge and connect cells. First described in immune cells, TNTs facilitate HIV-1 transfer and are found in various cell types, including neurons. We show that the microtubule-associated protein Tau, a key player in Alzheimer’s disease, is a bona fide constituent of TNTs. This is important because Tau appears beside filamentous actin and myosin 10 as a specific marker of these fine protrusions of membranes and cytosol that are difficult to visualize. Furthermore, we observed that exogenous Tau species increase the number of TNTs established between primary neurons, thereby facilitating the intercellular transfer of Tau fibrils. In conclusion, Tau may contribute to the formation and function of the highly dynamic TNTs that may be involved in the prion-like propagation of Tau assemblies.
Introduction Understanding the transmission of an infectious agent from one cell to another was a challenge of the last century. The involvement of cell-surface receptors has been shown, but other routes have also been described. Tunneling nanotubes (TNTs) form one such path. TNTs have been described in various cell types, including neuronal and immune cells. They are filamentous-actincontaining membranous structures with a diameter of 50 to 800 nm, not always linked to the substrate, and forming bridges that connect remote cells [1–6]. For instance, TNTs physically connect T cells, presenting a new pathway for HIV-1 transmission [7]. In such cells, the tip of the TNT is an active zone of actin cytoskeleton reorganization and contains ezrin, Exo70, myosin 10 and N-WASP, suggesting a regulation at the cellular level [8, 9]. Extrinsic factors such as arachidonic acid in endothelial cells [10], HIV-1 infection in macrophages [11], oxidative stress [12] and prion-like proteins (e.g.,
* Correspondence: [email protected]; [email protected] † Equal contributors 1 Université Lille, Inserm, CHU-Lille, UMR-S1172, Alzheimer & Tauopathies, 59000 Lille, France Full list of author information is available at the end of the article
Huntingtin fibrils, TDP-43) in neuronal cells [6, 13, 14] have been shown to trigger TNT formation. Many protein aggregates have prion-like properties: they can act as self-propagating templates. They disrupt cellular proteostasis, eventually leading to neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), or transmissible spongiform encephalopathies (TSEs) [15–17]. The exact mechanisms of the cell-tocell spreading of pathological species are still subject to in
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