|Less Is More...When You’re Talking About Aβ Toxicity
In 1906, Alois Alzheimer reported an interesting case of dementia at a meeting of the South-West German Society of Alienists (1). Four years later, Emil Kraepelin termed the disease “Alzheimer’s disease” (2). Since that time, a century of effort had been expended to elucidate the pathobiology of AD. For the last 100 years, only the histopathology was clear, namely plaques and tangles. It has only been in the last 25 years that the gene encoding the protein component of plaques, the amyloid-β protein (Aβ), was cloned and studies of the contribution of Aβ to AD have been undertaken. During this time, two successive “cascade” models have been embraced. The first, proposed by Hardy and Higgins in 1992 (3), comprised a cascade of pathogenetic events that began with amyloid fibril formation. The second, and current paradigm, I have referred to as the “oligomer cascade hypothesis” (4). This hypothesis suggests that Aβ oligomers, rather than fibrils, initiate the pathogenetic cascade leading to the neuronal injury and death...