The serine protease HTRA1 targets tau fibrils and provides a proteolytic barrier against pathogenic protein conformations

Tauopathies such as Alzheimer's disease, frontotemporal dementia with Parkinsonism, and other neurodegenerative diseases are classified as protein folding diseases because they share amyloid fibrils as a hallmark. Typically, amyloid fibrils accumulate and spread through tissue over time. It is assumed that this process is accelerated as protein quality control becomes overwhelmed in aged tissues. However, a deep understanding of how specific protein quality control factors interfere with fibril accumulation and thereby delay disease onset is lacking. Here, we demonstrate that the widely conserved serine protease HTRA1 is activated by tau fibrils, providing quantitative, topological, and temporal insights into the proteolytic degradation of both soluble and fibrillar tau. Live cell fluorescence microscopy demonstrates the interaction of HTRA1 with tau fibrils and their proteolytic degradation in cells. Our data highlight the potential of HTRA1 to act in a cell non-autonomous defense mechanism against the intercellular spread of pathogenic protein conformations.