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

Abstract

Extracellular plaques of β-amyloid (Aβ) and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer’s disease (AD). Plaques comprise Aβ fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of AD. Despite the significance of plaques to AD, oligomers are considered to be the principal toxic forms of Aβ1,2. Interestingly, many adverse responses to Aβ, such as cytotoxicity3, microtubule loss4, impaired memory and learning5, and neuritic degeneration6, are greatly amplified by tau expression. N-terminally truncated, pyroglutamylated (pE) forms of Aβ7,8 are strongly associated with AD, are more toxic than Aβ1–42 and Aβ1–40, and have been proposed as initiators of AD pathogenesis9,10. We now report a mechanism by which pE-Aβ may trigger AD. Aβ3(pE)-42 co-oligomerizes with excess Aβ1–42 to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ1–42 alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ3(pE)-42 plus 95% Aβ1–42 (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ1–42 monomers in the absence of additional Aβ3(pE)-42. LNOs isolated from human AD brain contained Aβ3(pE)-42, and enhanced Aβ3(pE)-42 formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau null background. We conclude that Aβ3(pE)-42 confers tau-dependent neuronal death and causes template-induced misfolding of Aβ1–42 into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ3(pE)-42 acts similarly at a primary step in AD pathogenesis.