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Soluble Fibrinogen Triggers Non-cell Autonomous ER Stress-Mediated Microglial-Induced Neurotoxicity
Thomas M Piers1, Emma East1, Claudio Villegas-Llerena1,2
1Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, London, United Kingdom.
Abstract:
Aberrant or chronic microglial activation is strongly implicated in neurodegeneration, where prolonged induction of classical inflammatory pathways may lead to a compromised blood-brain barrier (BBB) or vasculature, features of many neurodegenerative disorders and implicated in the observed cognitive decline. BBB disruption or vascular disease may expose the brain parenchyma to "foreign" plasma proteins which subsequently impact on neuronal network integrity through neurotoxicity, synaptic loss and the potentiation of microglial inflammation. Here we show that the blood coagulation factor fibrinogen (FG), implicated in the pathogenesis of dementias such as Alzheimer's disease (AD), induces an inflammatory microglial phenotype as identified through genetic microarray analysis of a microglial cell line, and proteome cytokine profiling of primary microglia. We also identify a FG-mediated induction of non-cell autonomous ER stress-associated neurotoxicity via a signaling pathway that can be blocked by pharmacological inhibition of microglial TNFα transcription or neuronal caspase-12 activity, supporting a disease relevant role for plasma components in neuronal dysfunction.
Insights
Blood coagulation factor fibrinogen triggers microglial inflammation and neurotoxicity, contributing to neurodegenerative diseases like Alzheimer's disease. This highlights the role of plasma proteins in cognitive decline and neuronal dysfunction.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Aberrant microglial activation is linked to neurodegeneration and cognitive decline.
- Blood-brain barrier disruption in neurodegenerative disorders allows plasma proteins into the brain, potentially causing neurotoxicity.
Purpose of the Study:
- To investigate the role of blood coagulation factor fibrinogen (FG) in microglial activation and neurotoxicity.
- To explore the signaling pathways involved in FG-mediated neurotoxicity and potential therapeutic targets.
Main Methods:
- Genetic microarray analysis of microglial cell lines.
- Proteome cytokine profiling of primary microglia.
- Pharmacological inhibition of microglial TNFα transcription and neuronal caspase-12 activity.
Main Results:
- Fibrinogen (FG) induces an inflammatory microglial phenotype.
- FG mediates non-cell autonomous ER stress-associated neurotoxicity.
- Microglial TNFα and neuronal caspase-12 are key in FG-induced neurotoxicity.
Conclusions:
- Plasma proteins like fibrinogen can drive neuroinflammation and neuronal dysfunction in neurodegenerative diseases.
- Targeting microglial TNFα and neuronal caspase-12 may offer therapeutic strategies for conditions involving BBB disruption and neurodegeneration.
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