Suggested mechanism of intraneuronal accumulation of Aβ in Alzheimer’s disease.

<p>Two pathways for the production of amyloid plaques are displayed. One involves the formation of neuritic plaques, which are characterized by the presence of densely packed Aβ fibrils, dystrophic neurites, reactive gliosis (astrocytes), extracellular filaments, activated microglial, and numerous other proteins. It is hypothesized that this neuritic plaque results from increased neuronal binding of Aβ, which forms fibrils that result in damaged neurons that follow a destructive pathway ultimately leading to the formation of the neuritic plaque. In contrast, Aβ that is not taken up by neurons forms Aβ protofibrils and fibrils and follows a protective pathway that results in the formation of diffuse/compact/dense core plaques. Substitution of the histidines of Aβ40 at positions 13 and 14 with glycine results in a significant decrease in neuronal binding, enhanced fibril formation, enhanced binding to fibrils, and equivalent plaque binding and thereby driving the histidine-substituted Aβ to the protective pathway involving the formation of diffuse/compact/dense core plaques. The plaque images are taken with permission from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008813#pone.0008813-Kennedy1" target="_blank">[45]</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008813#pone.0008813-Guntert1" target="_blank">[46]</a>.