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Inhibition of Aβ(1-40) fibril formation by cyclophilins

Marten Villmow1, Monika Baumann2, Miroslav Malesevic3

  • 1Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle (Saale), Germany.

The Biochemical Journal
|March 20, 2016
PubMed

Insights

Cyclophilins, including CypD and CypA, prevent amyloid beta fibril formation in early Alzheimer's disease stages. They bind to amyloid beta, shifting oligomers to monomers, thus inhibiting aggregation.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Molecular Biology

Background:

  • Cyclophilins interact with amyloid beta (Aβ) peptides, implicating them in early Alzheimer's disease.
  • Aβ binding to cyclophilin D (CypD) can lead to mitochondrial dysfunction.

Purpose of the Study:

  • To investigate the role of cyclophilins (CypD and CypA) in the in vitro fibril formation of Aβ(1-40).
  • To elucidate the mechanism by which cyclophilins inhibit Aβ aggregation.

Main Methods:

  • In vitro fibril formation assays.
  • SPOT peptide array and NMR titration experiments to confirm Aβ binding to CypD.
  • Isothermal titration calorimetry (ITC) to determine binding affinity.
  • Chemical cross-linking and NMR-detected hydrogen-deuterium exchange experiments.

Main Results:

  • CypD and CypA significantly suppressed Aβ(1-40) fibril formation at substoichiometric concentrations when added early.
  • Cyclophilin inhibitors (CsA and MM258) prevented this suppression.
  • Aβ(1-40) binds to the catalytic site of CypD, primarily through residues Lys(16)-Glu(22).
  • Aβ(16-20) peptide showed submicromolar IC50 and low-micromolar KD values for CypD and CypA.
  • Cyclophilins promote a shift from small Aβ(1-40) oligomers to monomeric species, inhibiting fibril formation.

Conclusions:

  • Cyclophilins actively inhibit Aβ(1-40) fibril formation by preventing oligomerization.
  • The interaction occurs at the catalytic site of cyclophilins, involving specific Aβ residues.
  • This mechanism offers a potential therapeutic target for Alzheimer's disease by modulating Aβ aggregation.
Keywords:
Alzheimer's disease peptideAβ(1–40)CypDamyloid fibrilscyclophilin

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