Mitochondria-derived superoxide mediates Aβ1-42 oligomer-induced neurotoxicity in primary brain cell cultures

Abstract

The accumulation of abnormal amyloid beta (Aβ) is involved in neurodegenerative diseases including Alzheimer's disease (AD). Recent research demonstrates importance of oxidative processes in AD pathogenesis. Mitochondria may produce reactive oxygen species (ROS) leading to mitochondrial dysfunction and neuronal death, however, the role of mitochondrial ROS in Aβ-induced neuronal death is not entirely understood. In our study, we investigated whether various Aβ 1-42 aggregates, small (<5 nm) Aβ 1-42 oligomers, large (>5 nm) Aβ 1-42 oligomers and insoluble Aβ 1-42 fibrils are capable to induce mitochondrial ROS generation in rat primary neuronal-glial cultures. Results with MitoSOX Red, a mitochondrial superoxide indicator, showed that only small Aβ 1-42 oligomers induced mitochondrial superoxide production in neurons and microglial cells. Larger Aβ 1-42 oligomers (>5 nm) and Aβ 1-42 fibrils did not cause mitochondrial ROS production. MitoTEMPO, a scavenger of mitochondrial superoxide, significantly decreased superoxide level in both, neurons and microglia after 1 hour incubation with small Aβ 1-42 oligomers, small Aβ 1-42 oligomer-induced neuronal death and loss and microglial proliferation was significantly decreased by Mito TEMPO after 24 hours. Our findings suggest that small Aβ oligomers can be taken up by neurons and microglia and cause production of mitochondrial superoxide leading to neuronal necrosis and microglial proliferation. Hence, pharmacological inhibition of mitochondrial ROS can protect neurons against small Aβ 1-42 oligomer-induced damage in AD.