Related Experiment Videos
Characterization of neuronal cell death induced by complement activation
Y Shen1, J A Halperin, L Benzaquen
1Neuroscience Department, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Insights
The complement system, crucial for immune defense, can cause cell death via the membrane attack complex (MAC). This study uses cell models to investigate complement-induced neuronal injury and its regulation.
Area of Science:
- Immunology
- Neuroscience
- Cell Biology
Background:
- The complement system is vital for immune defense, eliminating pathogens via membrane attack complex (MAC) formation.
- Classical complement pathway activation, initiated by C1q binding to immunoglobulins, leads to MAC assembly and cell lysis.
- Endogenous inhibitors regulate complement activity, distinguishing self from foreign targets and preventing host damage.
Purpose of the Study:
- To investigate complement system activation and its role in neuronal cell death.
- To explore the regulatory mechanisms of complement-mediated neurodegeneration, specifically homologous restriction.
- To present in vitro models for evaluating complement-induced cell injury.
Main Methods:
- Utilized two distinct cell lines as in vitro models.
- Induced complement activation via the classical pathway.
- Assessed complement-mediated cell injury and cell death.
Main Results:
- Demonstrated that complement activation induces neuronal cell death in vitro.
- Showed that homologous restriction plays a role in regulating this neurodegenerative process.
- Established the utility of the chosen cell lines for studying complement-induced damage.
Conclusions:
- Complement activation is a significant factor in neuronal cell death.
- Homologous restriction is a key regulatory mechanism in complement-mediated neurodegeneration.
- The developed in vitro models are valuable tools for studying complement-induced cell injury.
Abstract:
The complement system plays an important role in human immune defense mechanism. Its activation via either the classical or the alternative pathway can lead to the formation of membrane attack complex (MAC) and subsequently kills target cells. Activation of the classical pathway can be initiated with binding of C1q which is first factor of complement cascade to the Fc (fragment crystalline) region of immunoglobulin. This triggers a cascade of proteolytic events resulting in the activation of C5 convertase which cleaves C5 into C5b and C5a. The C5b then binds C6, C7, C8 to form a C5b-8 complex. Binding of C9 molecules to C5b-8 forms C5b-9, the MAC, which pore size increases as the number of C9 in the complex increases. If this membrane lesion persists and results in uncontrolled ion fluxes, the cells swell and eventually lyse. To restrict the activity of the complement system, endogenous complement inhibitors are available to regulate complement-mediated cytolysis. This enables the complement system to distinguish "self" from "foreign" and protect the host from inadvertent complement attack. Activation of the classical complement cascade has been reported in Alzheimer's disease and other neurodegenerative disorders. Recently, we demonstrated that complement activation causes neuronal cell death in vitro, and this neurodegenerative process is regulated by homologous restriction. In this article, we describe the use of two cell lines as in vitro models to evaluate cell injury/cell death induced by complement activation.