Alpha-synuclein activates BV2 microglia dependent on its aggregation state

Hoffmann, Alana; Ettle, Benjamin; Bruno, Ariane; Kulinich, Anna; Hoffmann, Anna-Carin; Wittgenstein, Julia von; Winkler, Jürgen; Xiang, Wei

doi:10.1016/j.bbrc.2016.09.109

Cited by 94 publications

(71 citation statements)

References 33 publications

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“…These observations are coherent with reports showing that the inflammatory potential of αS is dependent on the aggregation state of the protein (Hoffmann et al, 2016). Incidentally, the absence of effect of αSm confirms indirectly that the human recombinant αS that we prepared for this study was free of bacterial contaminants susceptible to induce glutamate release in microglial cells (Barger et al, 2007).…”

Section: Aggregated But Not Monomeric Forms Of αS Stimulate Glutamasupporting

confidence: 92%

“…Using a model system of purified microglial cell cultures, we established that amyloid fibrils of αS had the capacity to stimulate FIGURE 5 Dopamine prevents glutamate release induced by αSa in microglial cells through D 1 receptor activation. Concentrations comparable to those used by us in the present study were, however, required in other paradigms (Bussi et al, 2017;Hoffmann et al, 2016). Data are means ± SEM (n = 6).…”

Section: Aggregated But Not Monomeric Forms Of αS Stimulate Glutamamentioning

confidence: 60%

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Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

Pereira

Acuña

Hamadat

et al. 2018

Glia

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When activated, microglial cells have the potential not only to secrete typical proinflammatory mediators but also to release the neurotransmitter glutamate in amounts that may promote excitotoxicity. Here, we wished to determine the potential of the Parkinson's disease (PD) protein α‐Synuclein (αS) to stimulate glutamate release using cultures of purified microglial cells. We established that glutamate release was robustly increased when microglial cultures were treated with fibrillary aggregates of αS but not with the native monomeric protein. Promotion of microglial glutamate release by αS aggregates (αSa) required concomitant engagement of TLR2 and P2X7 receptors. Downstream to cell surface receptors, the release process was mediated by activation of a signaling cascade sequentially involving phosphoinositide 3‐kinase (PI3K) and NADPH oxidase, a superoxide‐producing enzyme. Inhibition of the Xc‐ antiporter, a plasma membrane exchange system that imports extracellular l‐cystine and exports intracellular glutamate, prevented the release of glutamate induced by αSa, indicating that system Xc‐ was the final effector element in the release process downstream to NADPH oxidase activation. Of interest, the stimulation of glutamate release by αSa was abrogated by dopamine through an antioxidant effect requiring D1 dopamine receptor activation and PI3K inhibition. Altogether, present data suggest that the activation of microglial cells by αSa may possibly result in a toxic build‐up of extracellular glutamate contributing to excitotoxic stress in PD. The deficit in dopamine that characterizes this disorder may further aggravate this process in a vicious circle mechanism.

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Section: Aggregated But Not Monomeric Forms Of αS Stimulate Glutamasupporting

confidence: 92%

Section: Aggregated But Not Monomeric Forms Of αS Stimulate Glutamamentioning

confidence: 60%

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

Pereira

Acuña

Hamadat

et al. 2018

Glia

View full text Add to dashboard Cite

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“…(Flavin et al ). α‐syn fibrillar assemblies also trigger neurodegeneration through chronic inflammation (Gustot et al ; Hoffmann et al ; Peralta Ramos et al ; Gribaudo et al ).…”

Section: Toxicity Of Fibrillar α‐Syn Speciesmentioning

confidence: 99%

“…neurodegeneration through chronic inflammation (Gustot et al 2015;Hoffmann et al 2016;Peralta Ramos et al 2019;Gribaudo et al 2019). While purified aSOs are more toxic toward SHSY5Y cells than fibrils on a weight basis, fibrils win out on a particle number basis as determined by a combination of analytical ultracentrifugation and quantitative length distribution measurements (Pieri et al 2012;Lorenzen et al 2014b).…”

Section: Toxicity Of Fibrillar A-syn Speciesmentioning

confidence: 99%

α‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities

Alam

Bousset

Melki

et al. 2019

Journal of Neurochemistry

240

205

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This review article provides an overview of the different species that α‐synuclein aggregates can populate. It also attempts to reconcile conflicting views regarding the cytotoxic roles of oligomers versus fibrils. α‐synuclein, while highly dynamic in the monomeric state, can access a large number of different assembly states. Depending on assembly conditions, these states can interconvert over different timescales. The fibrillar state is the most thermodynamically favored due to the many stabilizing interactions formed between each monomeric unit, but different fibrillar types form at different rates. The end distribution is likely to reflect kinetic partitioning as much as thermodynamic equilibra. In addition, metastable oligomeric species, some of which are on‐pathway and others off‐pathway, can be populated for remarkably long periods of time. Chemical modifications (phosphorylation, oxidation, covalent links to ligands, etc.) perturb these physical interconversions and invariably destabilize the fibrillar state, leading to small prefibrillar assemblies which can coalesce into amorphous states. Both oligomeric and fibrillar species have been shown to be cytotoxic although firm conclusions require very careful evaluation of particle concentrations and is complicated by the great variety and heterogeneity of different experimentally observed states. The mechanistic relationship between oligomers and fibrils remains to be clarified, both in terms of assembly of oligomers into fibrils and potential dissolution of fibrils into oligomers. While oligomers are possibly implicated in the collapse of neuronal homeostasis, the fibrillar state(s) appears to be the most efficient at propagating itself both in vitro and in vivo, pointing to critical roles for multiple different aggregate species in the progression of Parkinson’s disease (https://onlinelibrary.wiley.com/page/journal/14714159/homepage/virtual_issues.htm). This article is part of the Special Issue “Synuclein”.

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“…This outcome also sits strikingly alongside α‐synuclein possessing agonist activity for TLR2 (Kim et al ., ), that is, being a TNF‐inducing DAMP. Accordingly, a considerable literature shows that this protein, particularly in its aggregated state, induces TNF (Alvarez‐Erviti et al ., ; Beraud et al ., ; Hoffmann et al ., ). Thus, as for S100 proteins, HMGB1 and Aβ in an AD context (Clark and Vissel, ), it seems clear that α‐synuclein can function as a secondary, or positive feedback DAMP (de Haan et al ., ) (Figure ).…”

Section: New Tnf‐based Insightsmentioning

confidence: 99%

Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α‐synuclein, amyloid‐β and insulin resistance in neurodegenerative diseases

Clark

Vissel

2018

British J Pharmacology

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While cytokines such as TNF have long been recognized as essential to normal cerebral physiology, the implications of their chronic excessive production within the brain are now also increasingly appreciated. Syndromes as diverse as malaria and lead poisoning, as well as non‐infectious neurodegenerative diseases, illustrate this. These cytokines also orchestrate changes in tau, α‐synuclein, amyloid‐β levels and degree of insulin resistance in most neurodegenerative states. New data on the effects of salbutamol, an indirect anti‐TNF agent, on α‐synuclein and Parkinson's disease, APOE4 and tau add considerably to the rationale of the anti‐TNF approach to understanding, and treating, these diseases. Therapeutic advances being tested, and arguably useful for a number of the neurodegenerative diseases, include a reduction of excess cerebral TNF, whether directly, with a specific anti‐TNF biological agent such as etanercept via Batson's plexus, or indirectly via surgically implanting stem cells. Inhaled salbutamol also warrants investigating further across the neurodegenerative disease spectrum. It is now timely to integrate this range of new information across the neurodegenerative disease spectrum, rather than keep seeing it through the lens of individual disease states.

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Alpha-synuclein activates BV2 microglia dependent on its aggregation state

Cited by 94 publications

References 33 publications

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

α‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities

Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α‐synuclein, amyloid‐β and insulin resistance in neurodegenerative diseases

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