Induction of complement C9 messenger RNAs in human neuronal cells by inflammatory stimuli: relevance to neurodegenerative disorders

Neurons express proteins of the classical complement pathway, including C9. Both the mRNA and protein levels for C9 are sharply upregulated in brain a reas affected by Alzheimer's disease (AD). Since little is known about the signals that are responsible for this upregulation, we evaluated in human S H-SY5Y neuroblastoma cells the factors which stimulate C9 production. Inter feron-gamma, phorbol myristate acetate and interleukin-6 all stimulated C9 mRNA expression but the inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, as well as the anaphylatoxin C5a and the bacterial lip opolysaccharide, were ineffective. Immunohistochemical analysis of postmort em human brains for C9 protein demonstrated its presence in many cortical p yramidal neurons in AD, Down's syndrome, the parkinsonism dementia complex of Guam and pallido-ponto-nigral degeneration, as well as in thalamic neuro ns of progressive supranuclear palsy and ballooned neurons of Pick's diseas e. Since C9 is required for the membrane attack complex of complement to be come functional, interfering with signaling pathways that stimulate its pro duction could offer new therapeutic strategies for treating various neurode generative disorders. (C) 2001 Elsevier Science Inc. All rights reserved.