Prion-Like Behavior and Tau-dependent Cytotoxicity of Pyroglutamylated β-Amyloid

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 Aβ(1,2). Interestingly, many adverse responses to Aβ, such as cytotoxicity(3), microtubule loss(4), impaired memory and learning(5), and neuritic degeneration(6), are greatly amplified by tau expression. N-terminally truncated, pyroglutamylated (pE) forms of Aβ(7,8) are strongly associated with AD, are more toxic than Aβ(1–42) and Aβ(1–40), and have been proposed as initiators of AD pathogenesis(9,10). We now report a mechanism by which pE-Aβ may trigger AD. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1–42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1–42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1–42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1–42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human AD brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1–42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in AD pathogenesis.