Size dependent toxicity mechanisms of Aβ₁₋₄₂ aggregates in neuronal-glial cell cultures

Abstract

Aim: Amyloid beta (Aβ), a molecule implicated in pathogenesisi of Alzheimer's disease, is a highly aggregation-prone peptide which can form a variety of aggregates including solube Aβ oligomers and insoluble amyloid fibrils. The proposed mechanisms of neurotoxicity of Aβ peptides include perturbation of cellular membranes and disruption of Ca²⁺ homeostasis, promotion of inflammatory reactions or mitochondrial dysfunction. Part of the existing controversy may relate to the fact that Aβ toxicity depends on its assembly state. Methods: We used primary rat neuronal/glial cell cultures to analyze effects of various Aβ₁₋₄₂ assemblies such as monomers, small (1-3 nm) and large (5-10 nm) oligomers and Aβ₁₋₄₂ fibrils on viability of brain cells. Results: We found that small Aβ₁₋₄₂ oligomers at submicromolar concentration induced rapid neuronal necrosis whereas bigger Aβ₁₋₄₂ aggregates or monomers did not cause neuronal death. Small Aβ₁₋₄₂ oligomers-induced neuronal death was preceded by NMDA/AMPA-R-independent plasma membrane depolarization, mitochondrial superoxide generation, mitochondrial depolarization and NMDA-R-dependent glutamate relase into extracellular medium. In microglial cels, small Aβ oligomers caused NMDA-R-dependent depolarization of plasma membrane and mitochondrial superoxide generation. Astrocytes were resistant to small Aβ₁₋₄₂ assemblies-induced cell membrane perturbation, however, they showed increase in mitochondrial superoxide as well as mitochondrial depolarization. These effects were prevented in the presence of selective mitochondria-targeted antioxidant MitoTEMPO which also suppressed glutamate release to culture medium, NMDA-R and mitochondrial ROS can protect neurons from small Aβ₁₋₄₂ oligomer-induced damage in Alzheimer's disease. [...].