Dr Juan Polanco - QBI : "Understanding Tau Pathology Initiated by Exosomes and Vesicle-free Tau Seeds: A Quest for Therapeutic Targets"

Speaker: Dr Juan Polanco
Queensland Brain Institute
University of Queensland

Title: Understanding Tau Pathology Initiated by Exosomes and Vesicle-free Tau Seeds: A Quest for Therapeutic Targets

Tauopathies encompass a group of neurodegenerative disorders characterised by the aggregation of the microtubule-associated protein tau within neurons, forming pathological structures called neurofibrillary tangles. Notably, these tau aggregates are linked to the progression of two major forms of dementia, Alzheimer's disease and frontotemporal lobar degeneration with tau. The mechanisms underlying the generation of tau aggregates remain the subject of intensive investigations. Despite this, our understanding of the origins of dementia is still incomplete, and there is no cure for these neurological disorders that cause enormous social and economic burdens. However, we do know that tau aggregates can work as proteopathic 'seeds' that are capable of catalysing the misfolding and aggregation of physiological tau, inducing it to form oligomers and fibrils. This creates a self-perpetuating cycle wherein pathological amplification is driven by distorting the conformation of soluble tau. This process is not restricted to the neurons in which the tau seeds form. Indeed, tau seeds can propagate trans-synaptically and then be taken up by recipient neurons, or be released to the brain’s extracellular space. Prior to our studies, most groups focused entirely on tau aggregation triggered by vesicle-free tau seeds. However, I pioneered investigations which revealed that tiny extracellular vesicles (EVs), known as exosomes, can harbour tau seeds with the potential to initiate tau aggregation. This groundbreaking discovery has fuelled the exploration of the role of EVs in protein aggregate propagation across several neurodegenerative disorders.

In my talk, I will present an overview of the different studies that have significantly advanced our understanding of the pivotal roles played by exosomes and vesicle-free tau seeds in the initiation and propagation of tau pathology. These studies constitute our quest to uncover new targets for developing treatments by exploring the harmful effects, underlying processes, and regulators of tau aggregation at various subcellular compartments.