Induced expression of neuronal membrane attack complex and cell death by Alzheimer's beta-amyloid peptide.
beta-amyloid peptide (A beta) and complement-derived membrane attack complex (MAC) are co-localized in senile plaques of brains from Alzheimer's disease (AD) patients. But the relationship between A beta and complement activation is unclear. We have used human neurotypic cells, differentiated SH-SY5Y, as a model system to examine regulation of neuronal MAC expression and cell death by A beta. We demonstrated that mRNAs (C1q, C2, C3, C4, C5, C6, C7, C8 and C9) and proteins (C1q, C3 and C9) for the major components of the classical complement cascade are present in the SH-SY5Y neurotypic cells, indicating that neuronal cells can synthesize the necessary proteins required for MAC formation. Furthermore, immunocytochemical studies showed the A beta-induced neuronal MAC expression on the SH-SY5Y cells after CD59 was removed by PIPLC or blocked by anti-CD59 antibody. Meanwhile, increased A beta-induced neuronal cell death was observed following treatment with anti-CD59. Taken together, these results suggest that A beta activates neuronal complement cascade to induce MAC, and a deficiency of endogenous complement regulatory proteins, e.g., CD59, may increase the vulnerability of neurons to complement-mediated cytotoxicity.
Neuroscience Department, Abbott Laboratories, Abbott Park, IL 60064-3500, USA. yshen@mail.sunhealth.org
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D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000906:Antibodies / Q000276:immunology; D018957:CD59 Antigens / Q000032:analysis / Q000276:immunology; D016923:Cell Death / Q000502:physiology; D003167:Complement Activation / Q000502:physiology; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D000906:Antibodies; D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003165:Complement System Proteins; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase