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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:BackgroundAlzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD.MethodsHippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aβ-treated HEBSCs.ResultsNeurotoxicity induced by soluble Aβ1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention.ConclusionMicroglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity.

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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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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

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