Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease

Worldwide, Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and is characterized by unique pathological hallmarks in the brain, including plaques composed of amyloid beta-protein (A beta) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that A beta is responsible for the pathogenesis of AD (i.e., the amyloid hypothesis). Indeed, A beta molecules tend to aggregate, forming oligomers, protofibrils, and mature fibrils. However, while these A beta species form amyloid plaques of the type implicated in AD neurodegeneration, recent clinical trials designed to reduce the production of A beta and/or the plaque burden have not demonstrated clinical efficacy. In addition, recent studies using synthetic Afi peptides, cell culture models, Arctic transgenic mice, and human samples of AD brain tissues have suggested that the pre-fibrillar forms of A beta, particularly A beta protofibrils, may be the most critical species, compared with extracellular fibrillar forms. We recently reported that protofibrils of A beta(1-42) disturbed membrane integrity by inducing reactive oxygen species generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and synaptic toxicity. Therefore, the therapeutic reduction of protofibrils may prevent the progression of AD by ameliorating neuronal damage and cognitive dysfunction through multiple mechanisms.