Alzheimer’s Tau seeds-induced pathology enhances hippocampal extracellular diffusion

The extracellular space (ECS) is a complex, dynamic network occupying about 20% of the brain, filled with a cerebrospinal fluid-like solution rich in extracellular matrix (ECM) molecules. ECS properties regulate molecular diffusion, potentially influencing disease-associated protein spread in neurodegenerative diseases. However, its role in tau propagation remains unexplored. Using wild-type mice injected with tau seeds purified from Alzheimer's disease brain, we applied quantum dot single-particle tracking in live tissue to examine how tau pathology and inflammation influence extracellular diffusion. We observed increased diffusion associated with tau pathology in specific hippocampal regions. Additionally, diffusion profiles differed between cell-dense and cell-sparse areas. Astrocytes showed abnormal internalisation of proteoglycans, and matrix structural components were dysregulated, suggesting a link between altered ECM dynamics and enhanced diffusion. Increased diffusion and altered ECM dynamics might facilitate the spread of tau pathology.