Extracellular Diffusion of Tau Protein Is Slower Than Similar‐Sized IgG Protein and Dextran Polysaccharide in Entorhinal Cortex but Not in Prefrontal Cortex

In brain's extracellular space (ECS), proteins form an important part of endogenous macromolecular traffic. Each protein has unique diffusion characteristics governed by its size and, potentially, by charge-based interactions with extracellular matrix. The goal of this study was to provide quantitative data for extracellular diffusion of a human full-length Tau protein (Tau), a large intrinsically disordered protein with positively charged domains including specific heparan sulfate binding sites, in entorhinal cortex (EC) and prefrontal cortex (PFC), two brain regions affected by tauopathies. To this end, diffusion measurements with integrative optical imaging method in agarose gel and acute mouse brain slices determined diffusion permeability in the ECS of these two brain regions for Tau and for several control macromolecules: weakly negatively charged immunoglobulin G, neutral apolipoprotein E with a heparan sulfate binding site, and neutral or positively charged dextran polysaccharides. We found that diffusion permeability for Tau was similar in PFC and EC. In contrast, all other macromolecules were less hindered in EC with the exception of the positively charged dextran, suggesting that charge-based interactions between Tau and negatively charged extracellular matrix retard its extracellular diffusion. In conclusion, the extracellular diffusion of Tau in the EC is exceptionally slow in comparison to the other proteins and neutral dextrans. EC is the brain region linked to an onset of Alzheimer's disease, and the elements of extracellular microenvironment that govern Tau diffusion inside it will affect both its distribution and its clearance and could therefore play an important role in tauopathies such as the Alzheimer's disease.