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Trodusquemine enhances A?₄₂ aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

ABSTRACT: Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-? peptide (A?₄₂) are key pathogenic agents in Alzheimer's disease (AD). To investigate the relationship between A?₄₂ aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of A?₄₂-induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.

SUBMITTER: Limbocker R

PROVIDER: S-EPMC6333784 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

Limbocker Ryan R Chia Sean S Ruggeri Francesco S FS Perni Michele M Cascella Roberta R Heller Gabriella T GT Meisl Georg G Mannini Benedetta B Habchi Johnny J Michaels Thomas C T TCT Challa Pavan K PK Ahn Minkoo M Casford Samuel T ST Fernando Nilumi N Xu Catherine K CK Kloss Nina D ND Cohen Samuel I A SIA Kumita Janet R JR Cecchi Cristina C Zasloff Michael M Linse Sara S Knowles Tuomas P J TPJ Chiti Fabrizio F Vendruscolo Michele M Dobson Christopher M CM

Nature communications 20190115 1

Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ42) are key pathogenic agents in Alzheimer's disease (AD). To investigate the relationship between Aβ42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly ...[more]

PMID: 30644384

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Project description:Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer's disease (AD). In this disease, peripheral infiltrating macrophages play a substantial role in the clearance of amyloid beta (Aβ) peptides from the brain. Correspondingly, in patients suffering from AD, defects in the capacity of peripheral macrophages to engulf Aβ have been reported. The effects of carnosine on macrophages and oxidative stress associated with AD are consequently of substantial interest for drug discovery in this field. In the present work, a model of stress induced by Aβ1-42 oligomers was investigated using a combination of methods including trypan blue exclusion, microchip electrophoresis with laser-induced fluorescence, flow cytometry, fluorescence microscopy, and high-throughput quantitative real-time PCR. These assays were used to assess the ability of carnosine to protect macrophage cells, modulate oxidative stress, and profile the expression of genes related to inflammation and pro- and antioxidant systems. We found that pre-treatment of RAW 264.7 macrophages with carnosine counteracted cell death and apoptosis induced by Aβ1-42 oligomers by decreasing oxidative stress as measured by levels of intracellular nitric oxide (NO)/reactive oxygen species (ROS) and production of peroxynitrite. This protective activity of carnosine was not mediated by modulation of the canonical inflammatory pathway but instead can be explained by the well-known antioxidant and free-radical scavenging activities of carnosine, enhanced macrophage phagocytic activity, and the rescue of fractalkine receptor CX3CR1. These new findings obtained with macrophages challenged with Aβ1-42 oligomers, along with the well-known multimodal mechanism of action of carnosine in vitro and in vivo, substantiate the therapeutic potential of this dipeptide in the context of AD pathology.

Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-? peptide (A?). Monomeric soluble A? can switch from helicoidal to ?-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. A? can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that A? nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an A? analog containing a single residue (H to E) replacement that mimics the behavior of nitrated A? related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated A? oligomers was observed. Our results show that A? nitrotyrosination is a post-translational modification that increases A? synaptotoxicity. SIGNIFICANCE STATEMENT:We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-? (A?) favors the stabilization of highly toxic oligomers and inhibits the formation of A? fibrils. The nitrated A? oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

Dataset Information

Trodusquemine enhances A?₄₂ aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

Publications

Trodusquemine enhances Aβ<sub>42</sub> aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

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Dataset Information

Trodusquemine enhances A?42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

Publications

Trodusquemine enhances Aβ<sub>42</sub> aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Trodusquemine enhances A?₄₂ aggregation but suppresses its toxicity by displacing oligomers from cell membranes.