Butyrylcholinesterase attenuates amyloid fibril formation in vitro

Sophia Diamant, Erez Podoly, Assaf Friedler, Hagai Ligumsky, Oded Livnah, Hermona Soreq*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

In Alzheimer's disease, both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) colocalize with brain fibrils of amyloid-β (Aβ) peptides, and synaptic AChE-S facilitates fibril formation by association with insoluble Aβ fibrils. Here, we report that human BChE and BSP41, a synthetic peptide derived from the BChE C terminus, inversely associate with the soluble Aβ conformers and delay the onset and decrease the rate of Aβ fibril formation in vitro, at a 1:100 BChE/Aβ molar ratio and in a dose-dependent manner. The corresponding AChE synthetic peptide (ASP)40 peptide, derived from the homologous C terminus of synaptic human (h)AChE-S, failed to significantly affect Aβ fibril formation, attributing the role of enhancing this process to an AChE domain other than the C terminus. Circular dichroism and molecular modeling confirmed that both ASP40 and BChE synthetic peptide (BSP)41 are amphipathic α-helices. However, ASP40 shows symmetric amphipathicity, whereas BSP41 presented an aromatic tryptophan residue in the polar side of the C terminus. That this aromatic residue is causally involved in the attenuating effect of BChE was further supported by mutagenesis experiments in which (W8R) BSP41 showed suppressed capacity to attenuate fibril formation. In Alzheimer's disease, BChE may have thus acquired an inverse role to that of AChE by adopting imperfect amphipathic characteristics of its C terminus.

Original languageAmerican English
Pages (from-to)8628-8633
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number23
DOIs
StatePublished - 6 Jun 2006

Keywords

  • Alzheimer's disease
  • Aromatic
  • C-terminal peptide
  • Cholinesterase
  • Site-directed mutagenesis

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