Synthetic chaperone based on Hsp90-Tau interaction inhibits Tau aggregation and rescues physiological Tau-Microtubule interaction

Davide Lorenzo, Nicolo Bisi, Julia Kaffy, Lisa Marie Ramirez, Markus Zweckstetter, Olivier Lequin, Irene Garfagnini, Jinghui Luo, Yvonne Hannappel, Inga Ennen, Veronica Dodero, Norbert Sewald, Maria Luisa Gelmi, Nicolo Tonali (), Roland Brandt () and Sandrine Ongeri ()
Additional contact information
Davide Lorenzo: Bat. Henri Moissan
Nicolo Bisi: Bat. Henri Moissan
Julia Kaffy: Bat. Henri Moissan
Lisa Marie Ramirez: German Center for Neurodegenerative Diseases (DZNE)
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)
Olivier Lequin: LBM
Irene Garfagnini: Bat. Henri Moissan
Jinghui Luo: Department of Biology and Chemistry
Yvonne Hannappel: Bielefeld University
Inga Ennen: Bielefeld University
Veronica Dodero: Bielefeld University
Norbert Sewald: Bielefeld University
Maria Luisa Gelmi: Università degli Studi di Milano
Nicolo Tonali: Bat. Henri Moissan
Roland Brandt: Osnabrück University
Sandrine Ongeri: Bat. Henri Moissan

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The accumulation of intracellular aggregates of Tau protein is one main hallmark of Alzheimer’s disease (AD) and is the consequence of Tau conformational changes, increased phosphorylation, and self-association to form fibrillar aggregates. This pathological process prevents the physiological interaction of Tau with microtubules to the detriment of the structural integrity of neurons. In healthy cells, aberrant protein misfolding and aggregation are counteracted by chaperone proteins whose protective capacity decreases with age. The role of the chaperone Hsp90 and the mechanism by which it can prevent Tau aggregation are controversial. In this work, the strategy of mimicking Hsp90 through the design of the β-hairpin like peptidomimetic β-Hsp90, inspired by two Hsp90/Tau interaction sequences, is presented. β-Hsp90 inhibits Tau aggregation both in vitro and in cells, restoring Tau’s physiological interaction with microtubules. β-Hsp90, which interacts with the P1 region of Tau, is more effective than individual peptide sequences from the chaperone HSP90 and another β-hairpin mimic based on Tau sequences. Moreover, β-Hsp90 reduces AD-associated Aβ1-42 aggregation, offering the development of a dual inhibitor. This work paves the way for the design of new drugs targeting devastating untreated amyloid diseases, by mimicking physiological chaperones with small synthetic peptide drugs.

Date: 2025
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DOI: 10.1038/s41467-025-63824-1

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