Cellular pathogenesis of Alzheimer's disease

The author proposes that paired helical filaments, which contain the protei n tau in the fibrillar or beta-pleated sheet conformation, compete with mic rotubules for binding to nascent, soluble tau. Binding of nascent tau to ta u in the beta-pleated sheet conformation autocatalyzes the conformational c hange into the beta-pleated sheet conformation. As long as sufficient tau i s present to stabilize microtubules, neuronal function is; normal. However, because paired helical filaments are resistant to proteolysis, they accumu late and eventually bind the bulk of nascent tau. This results in progressi ve microtubule instability and eventually neuronal death. Senile plaques ar e involved in Alzheimer's disease pathogenesis in that they contain fibrill ar proteins which may function as heteronucleants, catalyzing the fibrillog enesis of other proteins such as tau. In this paradigm, apolipoprotein E4 s erves as a heteronucleant for fibrillogenesis of tau.