Home > Publications Database > Synthetic chaperone based on Hsp90-Tau interaction inhibits Tau aggregation and rescues physiological Tau-Microtubule interaction. > print

001     281530
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024 7 _ |a 10.1038/s41467-025-63824-1
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037 _ _ |a DZNE-2025-01148
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Di Lorenzo, Davide
|b 0
245 _ _ |a Synthetic chaperone based on Hsp90-Tau interaction inhibits Tau aggregation and rescues physiological Tau-Microtubule interaction.
260 _ _ |a [London]
|c 2025
|b Springer Nature
336 7 _ |a article
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520 _ _ |a 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.
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650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 7 |a HSP90 Heat-Shock Proteins
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 7 |a Peptide Fragments
|2 NLM Chemicals
650 _ 7 |a Protein Aggregates
|2 NLM Chemicals
650 _ 7 |a amyloid beta-protein (1-42)
|2 NLM Chemicals
650 _ 7 |a Molecular Chaperones
|2 NLM Chemicals
650 _ 7 |a Peptidomimetics
|2 NLM Chemicals
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
650 _ 2 |a tau Proteins: chemistry
|2 MeSH
650 _ 2 |a tau Proteins: genetics
|2 MeSH
650 _ 2 |a HSP90 Heat-Shock Proteins: metabolism
|2 MeSH
650 _ 2 |a HSP90 Heat-Shock Proteins: chemistry
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Microtubules: metabolism
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
650 _ 2 |a Protein Aggregation, Pathological: metabolism
|2 MeSH
650 _ 2 |a Peptide Fragments: metabolism
|2 MeSH
650 _ 2 |a Protein Binding
|2 MeSH
650 _ 2 |a Protein Aggregates: drug effects
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Phosphorylation
|2 MeSH
650 _ 2 |a Molecular Chaperones: metabolism
|2 MeSH
650 _ 2 |a Peptidomimetics: pharmacology
|2 MeSH
650 _ 2 |a Peptidomimetics: chemistry
|2 MeSH
700 1 _ |a Bisi, Nicolo
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700 1 _ |a Kaffy, Julia
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700 1 _ |a Ramirez, Lisa Marie
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700 1 _ |a Hannappel, Yvonne
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700 1 _ |a Ennen, Inga
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700 1 _ |a Dodero, Veronica
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700 1 _ |a Sewald, Norbert
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700 1 _ |a Gelmi, Maria Luisa
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700 1 _ |a Tonali, Nicolo
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700 1 _ |a Brandt, Roland
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700 1 _ |a Ongeri, Sandrine
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773 _ _ |a 10.1038/s41467-025-63824-1
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