The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation

4-Hydroxynonenal (4-HNE), formed as a consequence of oxidative stress, exists at increased concentrations in Alzheimer's disease (AD) patients and is found in amyloid beta peptide (A beta) plaques associated with AD. Although it remains an open question as to whether oxidative stress is a causative factor or a consequence of AD, we show here that 4-HNE, putatively resulting from the peroxidation of lipids, covalently modifies A beta, triggering its aggregation. These A beta modifications result from 1,4 conjugate addition and/or Schiff base formation, they occur at multiple locations on a single A beta peptide, and they result in covalent cross-linking of A beta peptides. The consequence of these reactions is that 4-HNE accelerates the formation of A beta protofibrils while inhibiting the production of straight, mature fibrils. Recent studies implicating A beta oligomers and protofibrils in the neurotoxic process that ultimately leads to AD suggest that the A beta aggregates induced by 4-HNE may be important in the pathogenesis of AD. These results provide further incentive to understand the role of oxidative stress and small-molecule A beta modifications in sporadic AD.