TY  - JOUR
AU  - Di Lorenzo, Davide
AU  - Bisi, Nicolo
AU  - Kaffy, Julia
AU  - Ramirez, Lisa Marie
AU  - Zweckstetter, Markus
AU  - Lequin, Olivier
AU  - Garfagnini, Irene
AU  - Luo, Jinghui
AU  - Hannappel, Yvonne
AU  - Ennen, Inga
AU  - Dodero, Veronica
AU  - Sewald, Norbert
AU  - Gelmi, Maria Luisa
AU  - Tonali, Nicolo
AU  - Brandt, Roland
AU  - Ongeri, Sandrine
TI  - Synthetic chaperone based on Hsp90-Tau interaction inhibits Tau aggregation and rescues physiological Tau-Microtubule interaction.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-01148
SP  - 8756
PY  - 2025
AB  - 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.
KW  - tau Proteins: metabolism
KW  - tau Proteins: chemistry
KW  - tau Proteins: genetics
KW  - HSP90 Heat-Shock Proteins: metabolism
KW  - HSP90 Heat-Shock Proteins: chemistry
KW  - Humans
KW  - Microtubules: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - Alzheimer Disease: metabolism
KW  - Protein Aggregation, Pathological: metabolism
KW  - Peptide Fragments: metabolism
KW  - Protein Binding
KW  - Protein Aggregates: drug effects
KW  - Animals
KW  - Phosphorylation
KW  - Molecular Chaperones: metabolism
KW  - Peptidomimetics: pharmacology
KW  - Peptidomimetics: chemistry
KW  - tau Proteins (NLM Chemicals)
KW  - HSP90 Heat-Shock Proteins (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - amyloid beta-protein (1-42) (NLM Chemicals)
KW  - Molecular Chaperones (NLM Chemicals)
KW  - Peptidomimetics (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41034231
C2  - pmc:PMC12489099
DO  - DOI:10.1038/s41467-025-63824-1
UR  - https://pub.dzne.de/record/281530
ER  -