Figure 6.

Hsp70 holdase function blocks tau aggregation, propagation, and toxicity. (a) Hsp70 inhibits the primary nucleation of tau by stabilizing monomeric and small oligomeric tau species. (b) Hsp70 sequesters growth competent seeds with high affinity and inhibits their elongation by monomer addition. (c) The binding of small oligomers by Hsp70 neutralizes their toxic properties such as membrane disruption. (d) Hsp70 may inhibit the spreading of seeds by sequestering fibrils and inhibiting their release and uptake. (e) The holdase function of Hsp70 may be the basis for the subsequent clearance of aberrant tau aggregates, e.g., via the proteasome, chaperone mediated autophagy (CMA), or direct disaggregation by Hsp70.