Neurotoxicity of acetylcholinesterase amyloid beta-peptide aggregates is dependent on the type of Abeta peptide and the AChE concentration present in the complexes.
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 (Abeta) fibrils and several proteins including acetylcholinesterase (AChE). AChE has been previously shown to stimulate the aggregation of Abeta1-40 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-Abeta complexes were found to be more toxic than those formed without the enzyme, for Abeta1-40 and Abeta1-42, but not for amyloid fibrils formed with AbetaVal18-Ala, a synthetic variant of the Abeta1-40 peptide. Of all the AChE-Abeta complexes tested the one containing the Abeta1-40 peptide was the most toxic. When increasing concentrations of AChE were used to aggregate the Abeta1-40 peptide, the neurotoxicity of the complexes increased as a function of the amount of enzyme bound to each complex. Our results show that AChE-Abeta1-40 aggregates are more toxic than those of AChE-Abeta1-42 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.
Muñoz
F J
FJ
Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago.
Inestrosa
N C
NC
D000110:Acetylcholinesterase / Q000378:metabolism / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016716:PC12 Cells; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D051381:Rats
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase