Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β

摘要: It is shown that the formation of amyloid-β oligomers, one histopathological signatures Alzheimer’s disease, can be triggered by small quantities a specifically truncated and post-translationally modified version amyloid-β. Here it demonstrated hypertoxic (Aβ) oligomers (pyroglutamylated) Aβ, called pEAβ. Previous studies have pE modification Aβ enhances its aggregation kinetics, toxicity resistance to degradation, but mechanistic explanation for these observations was lacking. This study shows pEAβ causes template-induced misfolding Aβ1–42 into structurally distinct propagate through prion-like mechanism. Tau expression required cytotoxicity similar molecules isolated from brains people with Alzheimer's disease. Extracellular plaques intraneuronal neurofibrillary tangles made tau are Plaques comprise fibrils assemble monomeric oligomeric intermediates, prognostic indicators Despite importance considered principal toxic forms amyloid-β1,2. Interestingly, many adverse responses amyloid-β, such as cytotoxicity3, microtubule loss4, impaired memory learning5, neuritic degeneration6, greatly amplified expression. Amino-terminally truncated, pyroglutamylated (pE) amyloid-β7,8 strongly associated more than residues 1–42 (Aβ1–42) Aβ1–40, been proposed initiators disease pathogenesis9,10. we report mechanism which pE-Aβ may trigger Aβ3(pE)–42 co-oligomerizes excess form metastable low-n (LNOs) far cytotoxic cultured neurons comparable LNOs alone. cytotoxicity, comprising 5% plus 95% (5% pE-Aβ) seed new multiple serial dilutions monomers in absence additional Aβ3(pE)–42. human brain contained Aβ3(pE)–42, enhanced mice neuron loss gliosis at 3 months, not tau-null background. We conclude confers tau-dependent neuronal death Our results raise possibility acts similarly primary step pathogenesis.