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

Nature | May 2, 2012

Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer's disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer's disease. 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 Alzheimer's disease 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 Alzheimer's disease pathogenesis.

Pubmed ID: 22660329 RIS Download

Mesh terms: Alzheimer Disease | Amyloid | Amyloid beta-Peptides | Animals | Disease Models, Animal | Glutamic Acid | Humans | Mice | Mice, Transgenic | Mutant Proteins | Peptide Fragments | Prions | tau Proteins

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Associated grants

  • Agency: NIA NIH HHS, Id: R01 AG033069
  • Agency: NIGMS NIH HHS, Id: T32 GM008136
  • Agency: NIA NIH HHS, Id: P50 AG016573
  • Agency: NIGMS NIH HHS, Id: GM008136
  • Agency: NIA NIH HHS, Id: P50AG16573
  • Agency: NIA NIH HHS, Id: R01AG033069
  • Agency: NIGMS NIH HHS, Id: T32 GM008136-25

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