A Structure-Toxicity Study of Aβ42 Reveals a New Anti-Parallel Aggregation Pathway

Amyloid beta (A beta) peptides produced by APP cleavage are central to the pathology of Alzheimer's disease. Despite widespread interest in this issue, the relationship between the auto-assembly and toxicity of these peptides remains controversial. One intriguing feature stems from their capacity to form anti-parallel beta-sheet oligomeric intermediates that can be converted into a parallel topology to allow the formation of protofibrillar and fibrillar A beta. Here, we present a novel approach to determining the molecular aspects of A beta assembly that is responsible for its in vivo toxicity. We selected A beta mutants with varying intracellular toxicities. In vitro, only toxic A beta (including wild-type A beta(42)) formed urea-resistant oligomers. These oligomers were able to assemble into fibrils that are rich in anti-parallel beta-sheet structures. Our results support the existence of a new pathway that depends on the folding capacity of A beta.