Characterization of neuronal cell death induced by complement activation.
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.
Shen
Y
Y
Neuroscience Department, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Halperin
J A
JA
Benzaquen
L
L
Lee
C M
CM
D000818:Animals; D001790:Blood Physiological Phenomena; D018957:CD59 Antigens / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D003167:Complement Activation / Q000502:physiology*; D003179:Complement C3b / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000494:pharmacology; D004338:Drug Combinations; D005455:Fluorescent Antibody Technique; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010716:Phosphatidylinositols / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D051381:Rats; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000494:pharmacology
D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D004338:Drug Combinations; D010716:Phosphatidylinositols; D003179:Complement C3b; D007770:L-Lactate Dehydrogenase; D010738:Type C Phospholipases