Alzheimer’s disease (AD) is an age‐related, progressive degenerative disorder that is characterized by synapse and neuron loss in the brain and the accumulation of protein‐containing deposits (referred to as ‘senile plaques’) and neurofibrillary tangles. Insoluble amyloid β‐peptide (Aβ) fibrillar aggregates found in extracellular plaques have long been thought to cause the neurodegenerative cascades of AD. However, accumulating evidence suggests that prefibrillar soluble Aβ oligomers induce AD‐related synaptic dysfunction. The size of Aβ oligomers is distributed over a wide molecular weight range (from < 10 kDa to > 100 kDa), with structural polymorphism in Aβ oligomers of similar sizes. Recent studies have demonstrated that Aβ can accumulate in living cells, as well as in extracellular spaces. This review summarizes current research on Aβ oligomers, focusing on their structures and toxicity mechanism. We also discuss possible formation mechanisms of intracellular and extracellular Aβ oligomers.

Amyloid fibrils are associated with more than 20 diseases, including Alzheimer's disease and type II diabetes. Insulin is a 51-residue polypeptide hormone, with its two polypeptide chains linked by one intrachain and two interchain disulfide bonds, and has long been known to self-assemble in vitro into amyloid fibrils. We demonstrate here that bovine insulin forms flexible filaments in the presence of a reducing agent, Tris (2-carboxyethyl) phosphine. The insulin filaments, possibly formed due to partial reduction of S-S bonds in insulin molecules, differ from intact insulin fibrils in terms of their secondary structure. The insulin filaments were determined to have an antiparallel beta-sheet structure, whereas the insulin fibrils have a parallel beta-sheet structure. Of importance, the cell toxicity of the insulin filaments was remarkably lower than that of the insulin fibrils. This finding supports the idea that cell toxicity of amyloids correlates with their morphology. The remarkably low toxicity of the filamentous structure should shed new light on possible pharmacological approaches to the various diseases caused by amyloid fibrils.

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