Juan Polanco

RESEARCH TEAM: Extracellular Vesicles and Tau Pathology

Tauopathies are neurodegenerative diseases characterised by the aggregation and fibrillisation of the microtubule-associated protein Tau, leading to the formation of neurofibrillary tangles (NFTs). These Tau lesions are common in Alzheimer’s disease, frontotemporal lobar degeneration with Tau, argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration. The prevailing theory suggests that Alzheimer's Tau pathology may result from the spread of misfolded Tau protein, known as "Tau seeds," through neuronal projections in the brain. These Tau seeds disrupt the conformation of soluble Tau protein in recipient neurons and exist in two forms: (i) vesicle-free Tau, such as free oligomers or fibrils, and (ii) exosomal Tau seeds, encapsulated within the membranes of secretory extracellular vesicles known as exosomes. While many research groups focus exclusively on vesicle-free Tau seeds, my team is dedicated to understanding how exosomal Tau seeds induce Tau pathology and how they differ from vesicle-free Tau seeds. Our research centres on three primary areas: 1) the role of exosomes in spreading Tau pathology in Alzheimer’s disease, 2) the mechanisms of exosomal cargo delivery into the cytosol, and 3) the genes and cellular processes associated with Tau aggregation. We have made significant contributions, including demonstrating that exosomes induce endolysosomal permeabilisation, allowing exosomal Tau seeds to escape into the cytosol (Acta Neuropathologica, 2021), and identifying the kinase Fyn as a key factor controlling NFT formation in neurons (Cell Reports, 2020). Our work has been featured on journal covers and has received positive attention in various research news articles.