Tau seeds in extracellular vesicles which proteforms? – TAUSEED

The initial clinical presentations of Alzheimer's disease (AD), progressive supranuclear palsy (PSP, parkinsonism) and Pick's disease (PiD, a subgroup of frontotemporal lobar degeneration) are sometimes similar: primary progressive aphasia, behavioural disorders, etc. Early diagnosis is therefore difficult, with a loss of chance for the patient to receive adequate care. These neurodegenerative diseases are tauopathies, characterised by the aggregation of tau proteins. Despite these similarities, tauopathies also have differences that we want to exploit to enable earlier diagnosis and improve their management. Within each tauopathy, tau pathology is first characterised by the aggregation of particular pathological tau variants. Secondly, each tauopathy has its own sequential and hierarchical neuroanatomical progression of neurodegeneration. Thus, each disease has its own specificity of progression: these neurodegeneration pathways have led to the prion-like tau propagation hypothesis. In this latter, there is a series of events that allow for the nucleation and subsequent spread of tau pathology. First, tau proteins adopt an abnormal conformation that leads to a prion-like misfolding of normal tau proteins into pathological proteins; this is the seeding. Subsequently, pathological species are secreted and then taken up by healthy cells where the nucleation cycle is repeated, thus transmitting the pathology. Finally, recent data suggest, for example, that the seed-competent tau species present in the human brain differ not only among tauopathies, but also within the same tauopathy (as demonstrated in AD). It is therefore essential to understand the underlying reasons for this heterogeneity before designing potential prognostic biomarkers that could significantly improve individual patient management.
The mode of propagation and the molecular species responsible for prion-like propagation are still poorly defined. Our project aims to characterise them. We will focus our study on extracellular vesicles (EVs) and free forms of tau found in biological fluids, extracellular fluids. On the one hand, lipoprotein EVs have the capacity to transfer many biologically active molecules between cells, and they are known to be deregulated in many conditions. On the other hand, specific receptors for free tau protein such as heparan sulfate proteoglycans or low density lipoprotein receptor-related protein1 have also been described in the literature and could therefore promote the susceptibility of certain cells to tau pathology. In addition, the secretion of tau in EVs and in free form has been validated in numerous cellular and animal models. However, very few data are available in humans. Here, a direct comparison between EVs and free forms of tau proteins isolated from the same human biological fluids (interstitial, cerebrospinal or plasma) of non-demented subjects and patients with tauopathy (AD, PSP and PiD) will be performed. Using these human samples, 1) we will assess the seeding properties of the isolated species and 2) we will generate tau profiles by state-of-the-art mass spectrometry, in particular on the species generated by protein misfolding cyclic amplification in order to improve the sensitivity of our assays. Our project aims to identify new targets for diagnosis and therapy.
In conclusion, this project aims to quantify and identify pro-seeding species of tau in biological fluids. These represent not only potentially useful prognostic biomarkers for patient stratification but also therapeutic targets for tau diseases.