The deposition of abnormal protein fibrils is the defining pathological feature of the “protein misfolding” disorders. Early-stage protein aggregates (“soluble oligomers”) may be responsible for some of the reported toxic effects of these fibrillogenic proteins. In the case of Aβ, which accumulates in the brain in Alzheimer’s disease (AD), these oligomers also have potent effects on long-term potentiation (LTP) and memory. A significant number of the aggregating proteins found in neurodegenerative disease can bind to redox-active metal ions and this interaction could explain some of their toxic properties. There is good evidence that Aβ can generate hydrogen peroxide (H

reactive oxygen species (ROS). We have confirmed this by employing the electron spin resonance spin-trapping technique, and have obtained similar results with α-synuclein, toxic fragments of the prion protein (PrP), the British dementia peptide (ABri) and amylin. Our data suggest that H

of aggregation and that it can be readily converted into hydroxyl radicals, by Fenton’s reaction. We hypothesize that a low-n oligomer could be the optimal size for ROS generation, and that a fundamental molecular mechanism underlying the pathogenesis of some of the protein misfolding disorders could be the direct production of ROS by soluble, early stage protein oligomers.