Alzheimer’s disease as oligomeropathy

Abstract

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and is characterized by pathological aggregates of amyloid β-protein (Aβ) and tau protein. On the basis of genetic evidence, biochemical data, and animal models, Aβ has been suggested to be responsible for the pathogenesis of AD (the amyloid hypothesis). Aβ molecules tend to aggregate to form oligomers, protofibrils, and mature fibrils. Although mature fibrils in the final stage have been thought to be the cause of AD pathogenesis, recent studies using synthetic Aβ peptides, a cell culture model, Aβ precursor protein transgenic mice models, and human samples, such as cerebrospinal fluids and postmortem brains of AD patients, suggest that pre-fibrillar forms (oligomers of Aβ) are more deleterious than are extracellular fibril forms. Based on this recent evidence showing that oligomers have a central role in the pathogenesis of AD, the term "oligomeropathy" could be used to define AD and other protein-misfolding diseases. In this review, I discuss recent developments in the "oligomer hypothesis" including our research findings regarding the pathogenesis of AD.