Toxicity in Rat Primary
Neurons through the Cellular
Oxidative Stress Induced by the Turn Formation at Positions 22 and
23 of Aβ42
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Abstract
The 42-mer amyloid β-protein (Aβ42) aggregates
to form
soluble oligomers that cause memory loss and synaptotoxicity in Alzheimer’s
disease (AD).
Oxidative stress is closely related to the pathogenesis of AD. We
previously identified the toxic conformer of Aβ42 with a turn
at positions 22 and 23 (“toxic turn”) by solid-state
NMR and demonstrated that a monoclonal antibody (11A1) against the
toxic turn in Aβ42 mainly detected the oligomer in the brains
of AD patients. Our recent study suggested that oxidative stress is
a key factor of the oligomerization and cognitive impairment induced
by Aβ overproduction in vivo. However, the involvement of the
toxic conformer in Aβ42-induced oxidative damage remains unclear.
To investigate this mechanism, we examined the levels of intracellular
reactive oxygen species (ROS) and neurotoxicity in rat primary neurons
using E22P-Aβ42, a mutant that induces a turn at positions 22
and 23, and E22V-Aβ42, a turn-preventing mutant. E22P-Aβ42,
but not E22V-Aβ42, induced greater ROS production than Wt-Aβ42
in addition to potent neurotoxicity. Interestingly, the formation
of the toxic conformer in both E22P-Aβ42 and Wt-Aβ42 probed
by the 11A1 antibody preceded Aβ42-induced neurotoxicity. Trolox
(a radical scavenger) and Congo red (an aggregation inhibitor) significantly
prevented the neurotoxicity and intracellular ROS induced by E22P-Aβ42
and Wt-Aβ42, respectively. These results suggest that Aβ42-mediated
toxicity is caused by the turn that favors toxic oligomers, which
increase generation of ROS