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

ABSTRACT: Extracellular plaques of amyloid-? and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-? 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-?. Interestingly, many adverse responses to amyloid-?, 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-? are strongly associated with Alzheimer's disease, are more toxic than amyloid-?, residues 1-42 (A?(1-42)) and A?(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-A? may trigger Alzheimer's disease. A?(3(pE)-42) co-oligomerizes with excess A?(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 A?(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% A?(3(pE)-42) plus 95% A?(1-42) (5% pE-A?) seed new cytotoxic LNOs through multiple serial dilutions into A?(1-42) monomers in the absence of additional A?(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained A?(3(pE)-42), and enhanced A?(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that A?(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of A?(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that A?(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.

SUBMITTER: Nussbaum JM

PROVIDER: S-EPMC3367389 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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

Nussbaum Justin M JM Schilling Stephan S Cynis Holger H Silva Antonia A Swanson Eric E Wangsanut Tanaporn T Tayler Kaycie K Wiltgen Brian B Hatami Asa A Rönicke Raik R Reymann Klaus K Hutter-Paier Birgit B Alexandru Anca A Jagla Wolfgang W Graubner Sigrid S Glabe Charles G CG Demuth Hans-Ulrich HU Bloom George S GS

Nature 20120502 7400

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 cytotoxicit ...[more]

PMID: 22660329

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Project description:Complement inhibitor C4b-binding protein (C4BP) is synthesized in liver and pancreas and composed of 7 identical alpha chains and one unique beta chain. We showed previously that C4BP binds islet amyloid polypeptide (IAPP) and affects fibril formation in vitro. Now we found that polymeric C4BP inhibited lysis of human erythrocytes incubated with monomeric IAPP while no erythrocyte lysis was observed after incubation with preformed IAPP fibrils. In contrast, monomeric alpha chain of C4BP had significantly reduced activity. Further, addition of monomeric IAPP to a rat insulinoma cell line (INS-1) resulted in decreased cell viability, which was restored in the presence of physiological concentrations of C4BP. Accordingly, addition of C4BP rescued the ability of INS-1 cells and isolated rat islets to respond to glucose stimulation with insulin secretion, which was impaired in the presence of IAPP alone. C4BP was internalized together with IAPP into INS-1 cells and therefore we aimed to study its effect on gene expression. Pathway analyses of mRNA expression microarray data indicated that cells exposed to C4BP and IAPP in comparison to IAPP alone increased expression of genes involved in cholesterol synthesis. Depletion of cholesterol through methyl-Î²-cyclodextrin or cholesterol oxidase abolished the protective effect of C4BP on IAPP cytotoxicity of INS-1 cells. Also, inhibition of phosphoinositide 3-kinase but not NF-ÎºB had a similar effect. Taken together, one of the mechanisms by which C4BP protects beta-cells from IAPP cytotoxicity is by enhancing cholesterol synthesis. The INS-1 cells were grown as 5 separate clones for 10 passages before plating in a 12-well plate (Nunc) at 100.000 cells per well and grown in complete RPMI 1640 medium to 70% confluency for approximately 48 h. The cells were then challenged by adding 77 Î¼M monomeric IAPP alone or together with C4BP (0.6 Î¼M). DMSO (1%) used as solvent for IAPP as well as C4BP (0.6 Î¼M) alone were used as controls. RNA was extracted after 10h incubation and analysis carried out using Rat Gene 2.0 array chip (Affymetrix).

Dataset Information

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

Publications

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

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