New pathogenic mechanisms of Tau

The accumulation of abnormally phosphorylated, abnormally conformed, and aggregated Tau protein is a central event in Alzheimer's disease and other tauopathies. We are investigating both how abnormal/pathological Tau protein spreads in the brain, thus contributing to the progression of these diseases, and how it promotes synaptic and neuronal loss. Regarding Alzheimer's disease, it is now accepted that pathological Tau protein spreads in the brain, at least in part, via so-called "prion-like" mechanisms. This is likely also the case for other tauopathies. This prion-like diffusion relies on the transfer of pathological Tau species ("Tau seeds") from an affected cell to a healthy recipient cell. Once internalized, these species recruit physiological Tau protein and induce its malformation, leading to the formation of aggregates (nucleation or "seeding").

This propagation therefore requires intercellular transfer of pathological Tau. Our team has shown that this transfer can occur through various mechanisms: secretion of free Tau, passage via nanotubes, or transport via extracellular vesicles (EVs). Recently, EVs isolated from brain tissue of patients with various tauopathies (Alzheimer's disease, progressive supranuclear palsy, and Pick's disease) were studied in vitro and in vivo to evaluate their nucleation capacity. This work showed that EVs from certain tauopathies (especially Alzheimer's disease) contain pathological forms of Tau capable of inducing a "pro-seeding" effect.

In this context, the team aims to characterize human brain-derived vesicles (VEs) in detail, analyzing both their overall protein content and the different forms of Tau they carry (isoforms, cleaved forms, with or without post-translational modifications). Furthermore, VE stratification is performed to identify the vesicular subtype(s) responsible for Tau propagation. To this end, small and large VEs are separated and studied distinctly.

In order to further investigate the mechanisms of propagation of Tau pathology in the brain and how the pathological Tau protein disrupts its function, we use cellular and animal models, some of which were developed in the laboratory.

In particular, in collaboration with Devrim Kilinc (IPL, Lille), we developed a cellular system to directly assess the toxicity of molecules (such as the abnormal proteins associated with Alzheimer's disease: Aβ and Tau) at the synapse level. In this system, neurons are cultured in a microfluidic device mounted on a microelectrode array (MEA). The microfluidic device consists of three chambers connected by fine microchannels. Neurons are seeded in the two lateral chambers. Under these conditions, axons from the first chamber and dendrites from the third chamber meet in the central chamber and form synapses. These synapses are functional. Thus, by comparing the activity of neurons in the two lateral chambers using recordings made with the microelectrodes (MEA), we observe that their activities are synchronized. It is then possible to apply the molecules to be tested in the synaptic chamber, the effect of which is evaluated by measuring the evolution of connectivity between the lateral chambers.