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@ARTICLE{DiLorenzo:281530,
      author       = {Di Lorenzo, Davide and Bisi, Nicolo and Kaffy, Julia and
                      Ramirez, Lisa Marie and Zweckstetter, Markus and Lequin,
                      Olivier and Garfagnini, Irene and Luo, Jinghui and
                      Hannappel, Yvonne and Ennen, Inga and Dodero, Veronica and
                      Sewald, Norbert and Gelmi, Maria Luisa and Tonali, Nicolo
                      and Brandt, Roland and Ongeri, Sandrine},
      title        = {{S}ynthetic chaperone based on {H}sp90-{T}au interaction
                      inhibits {T}au aggregation and rescues physiological
                      {T}au-{M}icrotubule interaction.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2025-01148},
      pages        = {8756},
      year         = {2025},
      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.},
      keywords     = {tau Proteins: metabolism / tau Proteins: chemistry / tau
                      Proteins: genetics / HSP90 Heat-Shock Proteins: metabolism /
                      HSP90 Heat-Shock Proteins: chemistry / Humans /
                      Microtubules: metabolism / Amyloid beta-Peptides: metabolism
                      / Alzheimer Disease: metabolism / Protein Aggregation,
                      Pathological: metabolism / Peptide Fragments: metabolism /
                      Protein Binding / Protein Aggregates: drug effects / Animals
                      / Phosphorylation / Molecular Chaperones: metabolism /
                      Peptidomimetics: pharmacology / Peptidomimetics: chemistry /
                      tau Proteins (NLM Chemicals) / HSP90 Heat-Shock Proteins
                      (NLM Chemicals) / Amyloid beta-Peptides (NLM Chemicals) /
                      Peptide Fragments (NLM Chemicals) / Protein Aggregates (NLM
                      Chemicals) / amyloid beta-protein (1-42) (NLM Chemicals) /
                      Molecular Chaperones (NLM Chemicals) / Peptidomimetics (NLM
                      Chemicals)},
      cin          = {AG Zweckstetter},
      ddc          = {500},
      cid          = {I:(DE-2719)1410001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41034231},
      pmc          = {pmc:PMC12489099},
      doi          = {10.1038/s41467-025-63824-1},
      url          = {https://pub.dzne.de/record/281530},
}