Amyloid Fibril Formation by a Synthetic Peptide from a Region of Human Acetylcholinesterase that Is Homologous to the Alzheimer's Amyloid-β Peptide

A region near the C-terminus of human acetylcholinesterase (AChE) is weakly homologous with the N-terminus of the Alzheimer's disease amyloid-β 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 as...

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Bibliographic Details
Published in:Biochemistry (Easton) 2002-11, Vol.41 (46), p.13539-13547
Main Authors: Cottingham, Matthew G, Hollinshead, Michael S, Vaux, David J. T
Format: Article
Language:English
Subjects:
Acetylcholinesterase - chemistry
Acetylcholinesterase - isolation & purification
Alzheimer Disease - metabolism
Amyloid beta-Peptides - chemistry
Amyloid beta-Peptides - metabolism
Animals
Biotinylation
Cell Division - physiology
Circular Dichroism
Coloring Agents - metabolism
Congo Red - metabolism
Fluorescent Dyes - metabolism
Humans
Microscopy, Electron
Neurofibrillary Tangles - metabolism
Neurofibrillary Tangles - ultrastructure
PC12 Cells - metabolism
Peptide Fragments - chemical synthesis
Peptide Fragments - pharmacology
Protein Binding
Rats
Thiazoles - metabolism
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Summary:A region near the C-terminus of human acetylcholinesterase (AChE) is weakly homologous with the N-terminus of the Alzheimer's disease amyloid-β 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 β-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 Aβ, 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 Aβ.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi0260334