Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder whose hallmark is the presence of senile plaques and neurofibrillary tangles, Senile plaques are mainly composed of amyloid beta-peptide (A beta) fibrils and several proteins including acetylcholinesterase (AChE), AChE has been previously shown to stimulate the aggregation of A beta(1-40) into amyloid fibrils, In the present work, the neurotoxicity of different amyloid aggregates formed in the absence or presence of AChE was evaluated in rat pheochromocytoma PC12 cells. Stable AChE-A beta complexes were found to be more toxic than those formed without the enzyme, for A beta(1-40) and A beta(1-42), but not for amyloid fibrils formed with A beta(Val18-->Ala), a synthetic variant of the A beta(1-40) peptide. Of all the AChE-A beta complexes tested the one containing the A beta(1-40) peptide was the most toxic, When increasing concentrations of AChE were used to aggregate the A beta(1-40) peptide, the neurotoxicity of the complexes increased as a function of the amount of enzyme bound to each complex. Our results shea that AChE-A beta(1-40) aggregates are more toxic than those of AChE-A beta(1-42) and that the neurotoxicity depends on the amount of AChE bound to the complexes, suggesting that AChE may play a key role in the neurodegeneration observed in Alzheimer brain. (C) 1999 Federation of European Biochemical Societies.