Clustering of Tau fibrils impairs the synaptic composition of α3‐Na+/K+‐ATPase and AMPA receptors

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. Synopsis Pathogenic fibrillar Tau remodel excitatory synaptic protein composition and imbalance neuronal homeostasis. Exogenous fibrillar‐Tau clusters at excitatory synapses. The membrane interactome of fibrillar Tau is identified. Fibrillar‐Tau interacts with Na + /K + ‐ATPase and GluA2‐AMPA receptor. Fibrillar Tau reduces Na + /K + ‐ATPase and increases GluA2‐AMPA receptor at synapses. Synuclein fibrils cross‐talk with fibrillar‐Tau at neuronal membrane. Graphical Abstract Proteomic identification of interactors of pathogenic Tau on neuronal membranes reveals unexpected cross talk between pathogenic α‐synuclein and Tau fibrils that regulates membrane depolarization and neurotransmission.