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000281530 1001_ $$aDi Lorenzo, Davide$$b0
000281530 245__ $$aSynthetic chaperone based on Hsp90-Tau interaction inhibits Tau aggregation and rescues physiological Tau-Microtubule interaction.
000281530 260__ $$a[London]$$bSpringer Nature$$c2025
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000281530 520__ $$aThe accumulation of intracellular aggregates of Tau protein is one main hallmark of Alzheimer's disease (AD) and is the consequence of Tau conformational changes, increased phosphorylation, and self-association to form fibrillar aggregates. This pathological process prevents the physiological interaction of Tau with microtubules to the detriment of the structural integrity of neurons. In healthy cells, aberrant protein misfolding and aggregation are counteracted by chaperone proteins whose protective capacity decreases with age. The role of the chaperone Hsp90 and the mechanism by which it can prevent Tau aggregation are controversial. In this work, the strategy of mimicking Hsp90 through the design of the β-hairpin like peptidomimetic β-Hsp90, inspired by two Hsp90/Tau interaction sequences, is presented. β-Hsp90 inhibits Tau aggregation both in vitro and in cells, restoring Tau's physiological interaction with microtubules. β-Hsp90, which interacts with the P1 region of Tau, is more effective than individual peptide sequences from the chaperone HSP90 and another β-hairpin mimic based on Tau sequences. Moreover, β-Hsp90 reduces AD-associated Aβ1-42 aggregation, offering the development of a dual inhibitor. This work paves the way for the design of new drugs targeting devastating untreated amyloid diseases, by mimicking physiological chaperones with small synthetic peptide drugs.
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000281530 650_7 $$2NLM Chemicals$$atau Proteins
000281530 650_7 $$2NLM Chemicals$$aHSP90 Heat-Shock Proteins
000281530 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000281530 650_7 $$2NLM Chemicals$$aPeptide Fragments
000281530 650_7 $$2NLM Chemicals$$aProtein Aggregates
000281530 650_7 $$2NLM Chemicals$$aamyloid beta-protein (1-42)
000281530 650_7 $$2NLM Chemicals$$aMolecular Chaperones
000281530 650_7 $$2NLM Chemicals$$aPeptidomimetics
000281530 650_2 $$2MeSH$$atau Proteins: metabolism
000281530 650_2 $$2MeSH$$atau Proteins: chemistry
000281530 650_2 $$2MeSH$$atau Proteins: genetics
000281530 650_2 $$2MeSH$$aHSP90 Heat-Shock Proteins: metabolism
000281530 650_2 $$2MeSH$$aHSP90 Heat-Shock Proteins: chemistry
000281530 650_2 $$2MeSH$$aHumans
000281530 650_2 $$2MeSH$$aMicrotubules: metabolism
000281530 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000281530 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000281530 650_2 $$2MeSH$$aProtein Aggregation, Pathological: metabolism
000281530 650_2 $$2MeSH$$aPeptide Fragments: metabolism
000281530 650_2 $$2MeSH$$aProtein Binding
000281530 650_2 $$2MeSH$$aProtein Aggregates: drug effects
000281530 650_2 $$2MeSH$$aAnimals
000281530 650_2 $$2MeSH$$aPhosphorylation
000281530 650_2 $$2MeSH$$aMolecular Chaperones: metabolism
000281530 650_2 $$2MeSH$$aPeptidomimetics: pharmacology
000281530 650_2 $$2MeSH$$aPeptidomimetics: chemistry
000281530 7001_ $$aBisi, Nicolo$$b1
000281530 7001_ $$00000-0002-1725-9268$$aKaffy, Julia$$b2
000281530 7001_ $$0P:(DE-2719)9001275$$aRamirez, Lisa Marie$$b3
000281530 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b4$$udzne
000281530 7001_ $$00000-0001-5307-3068$$aLequin, Olivier$$b5
000281530 7001_ $$aGarfagnini, Irene$$b6
000281530 7001_ $$00000-0002-7014-8153$$aLuo, Jinghui$$b7
000281530 7001_ $$aHannappel, Yvonne$$b8
000281530 7001_ $$aEnnen, Inga$$b9
000281530 7001_ $$00000-0001-7937-1880$$aDodero, Veronica$$b10
000281530 7001_ $$00000-0002-0309-2655$$aSewald, Norbert$$b11
000281530 7001_ $$00000-0003-0743-5499$$aGelmi, Maria Luisa$$b12
000281530 7001_ $$00000-0002-1435-5676$$aTonali, Nicolo$$b13
000281530 7001_ $$00000-0003-0101-1257$$aBrandt, Roland$$b14
000281530 7001_ $$00000-0002-2118-7324$$aOngeri, Sandrine$$b15
000281530 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-025-63824-1$$gVol. 16, no. 1, p. 8756$$n1$$p8756$$tNature Communications$$v16$$x2041-1723$$y2025
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