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

Abstract

A fundamental question about the pathogenesis of Alzheimer’s disease (AD) is how monomeric, nontoxic amyloid β-protein (Aβ) is converted to its toxic aggregates in the brain. The author previously identified a unique Aβ 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 Aβ (GAβ), 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 GAβ and validated that GAβ is endogenously generated in the brain and accelerates Aβ assembly by acting as a seed. Furthermore, the author provided a possibility that aging and the expression of apolipoprotein E4 facilitate Aβ assembly in the brain through an increase in the GM1 content in the neuronal membranes, which likely induces GAβ 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.