AbstractAlzheimer’s Disease is the most common neurodegenerative disorder. A hallmark of this disease is aggregation of the protein Tau into fibrillar tangles, which is ultimately linked to neuronal death 1,2. Oligomeric precursors of Tau fibrils are suspected to be the neurotoxic agent while fibrils themselves may be less harmful end products of the aggregation process 3,4. Evolutionary conserved families of molecular chaperones maintain protein homeostasis in healthy cells, preventing aggregation 5,6. Here, we investigate whether such chaperones could possibly reverse the aggregation reaction and dissolve Tau fibrils. Indeed we find that the human Hsp70 chaperone system disaggregates Tau fibrils. Both the bacterial and human Hsp70 chaperone systems disassemble fibril superstructures assembled of several fibril strands into single fibrils, indicating that this is an evolutionary conserved capacity of the Hsp70 system. However, further disaggregation of Tau fibrils into oligomers and even monomers is reserved to the human homologue. Thus, although bacteria possess an effective machinery to dissolve amorphous aggregates 7-9, we see that they do not have the means to disaggregate fibrils. Fibrillar aggregates, therefore, require different chaperone systems than amorphous aggregates, and this is a property acquired by Hsp70 during evolution. This makes the Hsp70 system an interesting target for novel drug strategies in Alzheimer.
A member of the Plasmodium falciparum PHIST family binds to the erythrocyte cytoskeleton component band 4.1