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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0386-4) contains supplementary material, which is available to authorized users.

Tau assemblies have prion‐like properties: they propagate from one neuron to another and amplify by seeding the aggregation of endogenous Tau. Although key in prion‐like propagation, the binding of exogenous Tau assemblies to the plasma membrane of naïve neurons is not understood. We report that fibrillar Tau forms clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+/K+‐ATPase (NKA) and AMPA receptors. The consequence of the clustering is a reduction in the amount of α3‐NKA and an increase in the amount of GluA2‐AMPA receptor at synapses. Furthermore, fibrillar Tau destabilizes functional NKA complexes. Tau and α‐synuclein aggregates often co‐exist in patients’ brains. We now show evidences for cross‐talk between these pathogenic aggregates with α‐synuclein fibrils dramatically enhancing fibrillar Tau clustering and synaptic localization. Our results suggest that fibrillar α‐synuclein and Tau cross‐talk at the plasma membrane imbalance neuronal homeostasis.