Figure 2.

Inhibition of tau aggregation and spreading. (A) Sites for direct binding of covalent tau aggregation inhibitors. There are two main groups that bind to the VQIINK and VQIVYK sequences (purple) or to the K residues (green). (B) Mechanisms of action of non-covalent tau aggregation inhibitors on tau aggregation. The red arrows point to the different points of inhibition. Molecular tweezers lower aggregation propensity by increasing reconfiguration rate, steric zipper blockers block the formation of the steric zippers structures, and oligomerization stabilizers block the process in the oligomer phase. Finally, PHFs and NFTs can be broken by aggregation disruptors. (C) Tau spreading can be inhibited by blocking exosomal release, by blocking tau interaction with HSPG, or by blocking endocytosis, either by blocking the receptors responsible for tau internalization or by blocking micropinocytosis.