COMPLEMENT C1-INHIBITOR EXPRESSION IN ALZHEIMERS-DISEASE

In situ and in vitro studies suggest that activation of locally produc ed complement factors may act as a mediator between amyloid deposits a nd neurodegenerative changes seen in Alzheimer's disease (AD). C1-este rase inhibitor (C1-Inh), which regulates activation of C1 of the compl ement classical pathway, can be detected immunohistochemically in its inactivated form in activated astrocytes and dystrophic neurites in AD plaque areas. In this study, designed to investigate the cellular sou rce of C1-Inh, C1-Inh was found to be secreted in a functionally activ e form by astrocytes cultured from postmortem human brain specimens as well as by neuroblastoma cell lines. Recombinant human interferon-gam ma (IFN-gamma), which stimulates C1-Inh synthesis in various cell type s, several-fold stimulated C1-Inh protein secretion by cultured human astrocytes derived from different regions of the central nervous syste m and by one (SK-N-SH) of two neuroblastoma cell lines (SK-N-SH and IM R-32) included in this study. In contrast to IFN-gamma, other cytokine s [interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF)-alpha ] that can be found in brain areas affected by AD, did not stimulate C 1-Inh secretion by astrocytes or neuroblastomas in vitro. This inabili ty to secrete C1-Inh is probably due to unresponsiveness at the transc riptional level, since C1-Inh secretion paralleled the expression of t he 2.1-kb C1-Inh mRNA. In situ hybridization with a C1-Inh RNA antisen se probe labeled neurons rather than astrocytes, suggesting a role for neurons as producers of complement regulatory proteins in vivo. Since IFN-gamma is apparently lacking in the brain parenchyma, and amyloid plaque-associated cytokines (IL-1 beta, IL-6, TNF-alpha) do not stimul ate C1-Inh expression in vitro, the nature of the stimulus responsible for neuronal C1-Inh expression in AD brains remains to be investigate d.