α-Synuclein activates stress signaling protein kinases in THP-1 cells and microglia

Klegeris, Andis; Pelech, Steven; Giasson, Benoit I.; Maguire, John A.; Zhang, Hong; McGeer, Edith G.; McGeer, Patrick L.

doi:10.1016/j.neurobiolaging.2006.11.013

Cited by 211 publications

(177 citation statements)

References 83 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…Microglia are the major resident immune cells of the central nervous system and are responsible to a large extent for elevated inflammatory reactions in disease-inflicted brains (51,52). Recent studies show that extracellular treatment with aggregated recombinant ␣-synuclein causes a variety of inflammatory responses in rodent and human microglia (15,(53)(54)(55). However, it remains to be addressed whether neuronderived ␣-synuclein can cause similar microglial responses.…”

Section: Discussionmentioning

confidence: 99%

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Lee

Suk²,

Patrick

et al. 2010

Journal of Biological Chemistry

746

726

View full text Add to dashboard Cite

Abnormal neuronal aggregation of ␣-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive ␣-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial ␣-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that ␣-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of ␣-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human ␣-synuclein. Furthermore, astrocytes that were exposed to neuronal ␣-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of ␣-synuclein. Together, these results suggest that astroglial ␣-synuclein pathology is produced by direct transmission of neuronal ␣-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.

show abstract

Section: Discussionmentioning

confidence: 99%

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Lee

Suk²,

Patrick

et al. 2010

Journal of Biological Chemistry

746

726

View full text Add to dashboard Cite

show abstract

“…Recent studies provided molecular details to the understanding of the neuroinflammaotry component in PD. It has been shown that the products secreted by damaged neurons ( [251,121]) aggregated alpha-synuclein or environmental toxins such as LPS are recognised by the macrophage antigen complex 1, Mac-1, a PRR expressed on microglia cells; in turn, Mac-1 activation is crucial for activation of NADPH oxidase, a membrane-bound enzyme that catalyses the production of superoxide anions, which are released in the extracellular space, and generates intracellular ROS, well known triggers of the inflammatory response ( [18,122,223,264]). NADPH oxidase is associated with neurodegenerative disorders and neuronal damage; it is activated in the brains of patients with PD [252].…”

Section: Animal Models Of Parkinson's Diseasementioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

278

206

View full text Add to dashboard Cite

a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

show abstract

“…[38][39][40][41][42][43] Moreover, the neurotoxicity induced by THP-1 cells in these experiments has been demonstrated to be very similar to that of human microglia derived from post mortem brain tissues. [44] Additionally, Combs et al [45] showed that stimulated primary murine microglia cause toxicity toward mouse embryonic neurons in a manner very similar to the actions of stimulated THP-1 cells.…”

Section: Discussionmentioning

confidence: 93%

Possible role of microparticles in neuroimmune signaling of microglial cells

Schindler¹,

Bajwa²,

Little³

et al. 2016

Self Cite

View full text Add to dashboard Cite

Aim: Submicron fragments termed microparticles (MPs), derived from all major central nervous system cell types including neurons and glia (microglia, astrocytes, oligodendrocytes), have emerged as novel intercellular signaling agents. This study tested the hypothesis that MPs derived from activated microglia, which represent the mononuclear phagocyte system in the brain, could induce pro-inflammatory and cytotoxic responses of microglia in an autocrine or paracrine manner. Methods: Human THP-1 monocytic cells were used to model human microglia. MPs derived from these cells were reapplied to THP-1 cells and their secretion of neurotoxins and cytokines was measured. Results: When exposed to lipopolysaccharide (LPS) or mitochondrial transcription factor A in combination with interferon (IFN)-γ, THP-1 cells released MPs. When reapplied to THP-1 cells, MPs induced the release of secretions that were toxic to human SH-SY5Y neuroblastoma cells, as well as monocyte chemoattractant protein-1. The cytotoxicity of THP-1 cells induced by MPs derived from IFN-γ plus LPS-treated THP-1 donor cells was enhanced in the presence of IFN-γ. The MPs released by THP-1 cells were not directly toxic towards SH-SY5Y cells. Conclusion: Our data support the hypothesis that activated microglia-derived MPs could act as signaling agents that are recognized by microglia to cause pro-inflammatory and cytotoxic responses. Key words:Microparticles, damage-associated molecular patterns, mononuclear phagocytes, glial cells, microglia, neurotoxicity, Alzheimer's disease, Parkinson's disease ABSTRACTArticle history:

show abstract

α-Synuclein activates stress signaling protein kinases in THP-1 cells and microglia

Cited by 211 publications

References 83 publications

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Possible role of microparticles in neuroimmune signaling of microglial cells

Contact Info

Product

Resources

About