Amyloid fibril formation by a synthetic peptide from a region of human acetylcholinesterase that is homologous to the Alzheimer's amyloid-beta peptide.
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.
Cottingham
Matthew G
MG
Sir William Dunn School of Pathology, University of Oxford, UK.
Hollinshead
Michael S
MS
Vaux
David J T
DJ
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000302:isolation & purification; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D019921:Biotinylation; D002455:Cell Division / Q000502:physiology; D002942:Circular Dichroism; D004396:Coloring Agents / Q000378:metabolism; D003224:Congo Red / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D008854:Microscopy, Electron; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000648:ultrastructure; D016716:PC12 Cells / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D004396:Coloring Agents; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013844:Thiazoles; C009462:thioflavin T; D003224:Congo Red; D000110:Acetylcholinesterase