Fig. 7. Proposed model for the intra- and extracellular action of the S100B chaperone on tau.

The cartoon summarizes regulatory intra- (left) and extracellular (right) interactions established between S100B and tau. Inside cells, S100B operates as a microtubule-regulating factor, likely acting as a protective holdase that mitigates proteotoxic tau, upon its release following microtubule destabilization. Extracellular S100B is increased in the AD brain from early disease stages and is abundantly secreted by astrocytes nearby tau-positive inclusions. In this context, S100B performs as a chaperone inhibiting aggregation through interactions established with released proteotoxic tau, thus contributing to decrease seeding reactions and pathological cell-to-cell spreading.