Study of tau strains to understand the phenotypic diversity of Alzheimer’s disease: A step toward personalized therapies

Dementia represents a major challenge for our ageing societies. The number of citizens suffering from dementia in the EU is expected to reach 19 millions by 2050. Alzheimer’s disease (AD) is responsible for the vast majority of dementia cases. However there is still not a single available treatment that modifies the course of disease. Therefore, the development of innovative approaches to better understand the pathophysiology and ultimately treat patients must be a priority. This project aims to understand the determinants of the diversity of AD clinical phenotypes through the deep analysis of pathological variants of the tau protein. As the accumulation of Aβ peptide has long been considered a causative event in AD, most therapeutic approaches have targeted Aβ metabolism, but unsuccessfully. Modern biomarkers, have confirmed that the brain deposition of tau pathology, the other hallmark of AD, correlates much better with human cognition and neurodegeneration. Recently, it was shown that tau behaves like a prion and can spread from one neuron to another. Moreover, tau strains or conformers seem to template native tau and propagate the pathological conformation with high fidelity. Discrete tau strains generate distinct aggregates morphology or patterns of neuronal vulnerability. I postulate that different strains of tau are responsible for the variability of AD and may determine the progression rate, gender differences or clinical expression. Therefore, my objective is to develop the technologies to identify tau strains signatures in distinct AD phenotypes. In particular, I plan to develop and optimize biosensor cell lines that sensitively detect tau strains from human brain samples and cerebrospinal fluid, and characterize respective repertoire of tau strains. Understanding AD heterogeneity would potentially increase our ability to take care of every individual patient. In addition, this work could lead to the development of biomarkers and novel targeted therapies.