Journal Article

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

Reymann, Klaus, Schilling, Stephan, Hutter-Paier, Birgit, Wangsanut, Tanaporn, Tayler, Kaycie, Graubner, Sigrid, Bloom, George S., Cynis, Holger, Swanson, Eric, Hatami, Asa, Silva, Antonia, Glabe, Charles G., Rönicke, Raik, Jagla, Wolfgang, Alexandru, Anca, Nussbaum, Justin M., Wiltgen, Brian, Demuth, Hans-Ulrich

2012

Overview

It is shown that the formation of amyloid-β oligomers, one of the histopathological signatures of Alzheimer’s disease, can be triggered by small quantities of a specifically truncated and post-translationally modified version of amyloid-β. Hypertoxic amyloid variants Here it is demonstrated that the formation of hypertoxic amyloid-β (Aβ) oligomers can be triggered by small quantities of a specifically truncated and post-translationally modified (pyroglutamylated) version of Aβ, called pEAβ. Previous studies have shown that pE modification of Aβ enhances its aggregation kinetics, toxicity and resistance to degradation, but a mechanistic explanation for these observations was lacking. This study shows that pEAβ causes template-induced misfolding of Aβ 1–42 into small hypertoxic structurally distinct oligomers that propagate through a prion-like mechanism. Tau expression is required for the cytotoxicity of these oligomers, and similar molecules can be isolated from the brains of people with Alzheimer's disease. 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 1 , 2 . Interestingly, many adverse responses to amyloid-β, such as cytotoxicity 3 , microtubule loss 4 , impaired memory and learning 5 , and neuritic degeneration 6 , are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β 7 , 8 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 9 , 10 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1697 / 631/45/535 / 631/80/470/460 / 692/699/375/365/1283 / Adult and adolescent clinical studies / Alzheimer Disease - metabolism / Alzheimer's disease / Amyloid - chemistry / Amyloid - drug effects / Amyloid - metabolism / Amyloid - toxicity / Amyloid beta-Peptides - chemistry / Amyloid beta-Peptides - genetics / Amyloid beta-Peptides - metabolism / Amyloid beta-Peptides - toxicity / Amyloid beta-protein / Animals / Biological and medical sciences / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Disease Models, Animal / Glutamic Acid - chemistry / Glutamic Acid - metabolism / Humanities and Social Sciences / Humans / letter / Medical research / Medical sciences / Medicine, Experimental / Mice / Mice, Transgenic / multidisciplinary / Mutant Proteins - chemistry / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutant Proteins - toxicity / Neurology / Organic mental disorders. Neuropsychology / Peptide Fragments - chemistry / Peptide Fragments - genetics / Peptide Fragments - metabolism / Peptide Fragments - toxicity / Physiological aspects / Prions / Prions - chemistry / Prions - metabolism / Prions - toxicity / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Science / Science (multidisciplinary) / tau Proteins - deficiency / tau Proteins - genetics / tau Proteins - metabolism