Neurotoxicity of acetylcholinesterase amyloid β-peptide aggregates is dependent on the type of Aβ peptide and the AChE concentration present in the complexes

AbstractAlzheimer’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 β-peptide (Aβ) fibrils and several proteins including acetylcholinesterase (AChE). AChE has been previously shown to stimulate the aggregation of Aβ1–40 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-Aβ complexes were found to be more toxic than those formed without the enzyme, for Aβ1–40 and Aβ1–42, but not for amyloid fibrils formed with AβVal18→Ala, a synthetic variant of the Aβ1–40 peptide. Of all the AChE-Aβ complexes tested the one containing the Aβ1–40 peptide was the most toxic. When increasing concentrations of AChE were used to aggregate the Aβ1–40 peptide, the neurotoxicity of the complexes increased as a function of the amount of enzyme bound to each complex. Our results show that AChE-Aβ1–40 aggregates are more toxic than those of AChE-Aβ1–42 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