Cellular pathogenesis of Alzheimer's disease

The author proposes that paired helical filaments, which contain the protein tau in the fibrillar or beta-pleated sheet conformation, compete with microtubules for binding to nascent, soluble tau. Binding of nascent tau to tau in the beta-pleated sheet conformation autocatalyzes the conformational change into the beta-pleated sheet conformation. As long as sufficient tau is present to stabilize microtubules, neuronal function is normal. However, because paired helical filaments are resistant to proteolysis, they accumulate and eventually bind the bulk of nascent tau. This results in progressive microtubule instability and eventually neuronal death. Senile plaques are involved in Alzheimer's disease pathogenesis in that they contain fibrillar proteins which may function as heteronucleants, catalyzing the fibrillogenesis of other proteins such as tau. In this paradigm, apolipoprotein E4 serves as a heteronucleant for fibrillogenesis of tau.