GM1 Ganglioside and the Seeding of Amyloid in Alzheimer’s Disease: Endogenous Seed for Alzheimer Amyloid

A fundamental question about the pathogenesis of Alzheimer's disease (AD) is how monomeric, nontoxic amyloid beta-protein (Abeta) is converted to its toxic aggregates in the brain. The author previously identified a unique Abeta species in the AD brain, which is characterized by its binding to GM1 ganglioside (GM1). On the basis of the molecular characteristics of GM1-bound Abeta (GAbeta), the author hypothesized that GM1 plays a critical role in the process. The author recently examined this possibility using a novel monoclonal antibody raised against purified GAbeta and validated that GAbeta is endogenously generated in the brain and accelerates Abeta assembly by acting as a seed. Furthermore, the author provided a possibility that aging and the expression of apolipoprotein E4 facilitate Abeta assembly in the brain through an increase in the GM1 content in the neuronal membranes, which likely induces GAbeta generation. The author's results imply a mechanism underlying the onset of AD and also provide a new insight into development of novel therapeutic strategy.