Amyloid fibril formation by a synthetic peptide from a region of human acetylcholinesterase that is homologous to the Alzheimer's amyloid-beta peptide.

Journal article

A region near the C-terminus of human acetylcholinesterase (AChE) is weakly homologous with the N-terminus of the Alzheimer's disease amyloid-beta peptide. We report that a 14-amino acid synthetic polypeptide whose sequence corresponds to residues 586-599 of the human synaptic or T form of AChE assembles into amyloid fibrils under physiological conditions. The fibrils have all the classical characteristics of amyloid: they have a diameter of 6-7 nm and bind both Congo red and thioflavin-T. Furthermore, the kinetics of assembly indicate that fibril formation proceeds via a two-step nucleation-dependent polymerization pathway, and a transition in the peptide conformation from random coil to beta-sheet is observed during fibril formation using far-UV circular dichroism spectroscopy. We also show that the peptide in aggregated fibrillar form has a toxic effect upon PC-12 cells in vitro. AChE normally resides mainly on cholinergic neuronal membranes, but is abnormally localized to senile plaques in Alzheimer's disease. Recently, an in vitro interaction between AChE and A beta, the principal constituent of the amyloid fibrils in senile plaques, has been documented. The presence of a fibrillogenic region within AChE may be relevant to the interaction of AChE with amyloid fibrils formed by Abeta.

Authors: Cottingham, MG; Hollinshead, MS; Vaux, D

• Publication status: Published
• Journal: Biochemistry
• Volume: 41
• Issue: 46
• Pages: 13539-13547
• Publication date: 2002-11-01
• DOI: 10.1021/bi0260334
• EISSN: 1520-4995
• ISSN: 0006-2960
• Language: English
• Keywords: Biotinylation; Amyloid beta-Peptides; Neurofibrillary Tangles; Peptide Fragments; Cell Division; Humans; Rats; Congo Red; PC12 Cells; Fluorescent Dyes; Microscopy, Electron; Acetylcholinesterase; Thiazoles; Coloring Agents; Circular Dichroism; Protein Binding; Animals; Alzheimer Disease