Dorian Bruch

Seeding of Tau Protein Aggregation

Neurodegenerative diseases (NDs), like Alzheimer’s, are debilitating diseases that represent a growing economic and societal burden in developed countries. Yet, there are no cures because they are poorly understood. Alzheimer’s is known to be caused by diseased protein fibrils in the intracellular matrix, composed of Tau protein subunits. These fibrils clog neurons and interfere with axonal transport systems, eventually leading to cell death. Current research suggests that brain damage in Alzheimer’s patients spreads from neuron to neuron. It is believed that the spreading occurs through seeding, in which a small piece of fibril (the seed) recruits surrounding naïve monomers to form mature fibrils. However, the mechanism of this seeding is unclear. It has been shown that tau fibrils extracted from diseased brains are active seeds, while fibrils produced in vitro are not. Our goal is to know both the mechanism behind seeding, and what allows in vivo fibers to seed but not in vitro fibers. We tested several experimental parameters such as tau mutations, pH, salt concentration, and seed size to find seeding prone conditions. We quantified fibril formation through Thioflavin T fluorescence, which indicates the presence of tau fibrils. We aim to shed light on the seeding mechanism and ultimately at engineering potent in vitro seeds that would help to understand the spread of tau fibrils in NDs.