How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimers disease brain by a strain-relief mechanism

Hou, K.; Ge, P.; Sawaya, M. R.; Dolinsky, J. L.; Yang, Y.; Jiang, Y. X.; Lutter, L.; Boyer, D. R.; Cheng, X.; Pi, J.; Zhang, J.; Lu, J.; Yang, S.; Yu, Z.; Feigon, J.; Eisenberg, D. S.

doi:10.1101/2024.03.25.586668

bioRxiv · 10.1101/2024.03.25.586668

How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimers disease brain by a strain-relief mechanism

Hou, K.·Ge, P.·Sawaya, M. R.·Dolinsky, J. L.·Yang, Y.·Jiang, Y. X.·Lutter, L.·Boyer, D. R.·Cheng, X.·Pi, J.·Zhang, J.·Lu, J.·Yang, S.·Yu, Z.·Feigon, J.·Eisenberg, D. S.

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Abstract

Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimers disease (AD). Previously we found that in vitro the D-peptide D-TLKIVWC disassembles tau fibrils from AD brains (AD-tau) into benign segments with no energy source present beyond ambient thermal agitation. This disassembly by a short peptide was unexpected, given that AD-tau is sufficiently stable to withstand disassembly in boiling SDS detergent. To consider D peptide-mediated disassembly as a potential therapeutic for AD, it is essential to understand the mechanism and energy source of the disassembly action. We find assembly of D-peptides into amyloid-like fibrils is essential for tau fibril disassembly. Cryo-EM and atomic force microscopy reveal that these D-peptide fibrils have a right-handed twist and embrace tau fibrils which have a left-handed twist. In binding to the AD-tau fibril, the oppositely twisted D-peptide fibril produces a strain, which is relieved by disassembly of both fibrils. This strain-relief mechanism appears to operate in other examples of amyloid fibril disassembly and provides a new direction for the development of first-in-class therapeutics for amyloid diseases.

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Hou, K., Ge, P., Sawaya, M. R., Dolinsky, J. L., Yang, Y., Jiang, Y. X., Lutter, L., Boyer, D. R., Cheng, X., Pi, J., Zhang, J., Lu, J., Yang, S., Yu, Z., Feigon, J., Eisenberg, D. S.. 2024-03-29. How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimers disease brain by a strain-relief mechanism. https://doi.org/10.1101/2024.03.25.586668

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