Complement C1-inhibitor expression in Alzheimer’s disease (original) (raw)
Abstract
In situ and in vitro studies suggest that activation of locally produced complement factors may act as a mediator between amyloid deposits and neurodegenerative changes seen in Alzheimer’s disease (AD). C1-esterase inhibitor (C1-Inh), which regulates activation of C1 of the complement 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 source of C1-Inh, C1-Inh was found to be secreted in a functionally active form by astrocytes cultured from postmortem human brain specimens as well as by neuroblastoma cell lines. Recombinant human interferon-γ (IFN-γ), which stimulates C1-Inh synthesis in various cell types, several-fold stimulated C1-Inh protein secretion by cultured human astrocytes derived from different regions of the central nervous system and by one (SK-N-SH) of two neuroblastoma cell lines (SK-N-SH and IMR-32) included in this study. In contrast to IFN-γ, other cytokines [interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α] that can be found in brain areas affected by AD, did not stimulate C1-Inh secretion by astrocytes or neuroblastomas in vitro. This inability to secrete C1-Inh is probably due to unresponsiveness at the transcriptional level, since C1-Inh secretion paralleled the expression of the 2.1-kb C1-Inh mRNA. In situ hybridization with a C1-Inh RNA antisense probe labeled neurons rather than astrocytes, suggesting a role for neurons as producers of complement regulatory proteins in vivo. Since IFN-γ is apparently lacking in the brain parenchyma, and amyloid plaque-associated cytokines (IL-1β, IL-6, TNF-α) do not stimulate C1-Inh expression in vitro, the nature of the stimulus responsible for neuronal C1-Inh expression in AD brains remains to be investigated.
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Authors and Affiliations
- Department of Psychiatry, Research Institute Neurosciences Vrije Universiteit, Vrije Universiteit, Graduate School Neurosciences Amsterdam, Amsterdam, The Netherlands, , , , , , NL
R. Veerhuis & P. Eikelenboom - Department of Pathology, Research Institute Neurosciences Vrije Universiteit, Vrije Universiteit, Graduate School Neurosciences Amsterdam, Amsterdam, The Netherlands, , , , , , NL
I. Janssen, J. J. M. Hoozemans & C. J. A. De Groot - Department of Pathophysiology of Plasma Proteins, Central Laboratory for Blood Transfusion, Amsterdam, The Netherlands, , , , , , NL
C. E. Hack
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- R. Veerhuis
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Received: 18 December 1997 / Revised, accepted: 11 March 1998
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Veerhuis, R., Janssen, I., Hoozemans, J. et al. Complement C1-inhibitor expression in Alzheimer’s disease.Acta Neuropathol 96, 287–296 (1998). https://doi.org/10.1007/s004010050896
- Issue Date: August 1998
- DOI: https://doi.org/10.1007/s004010050896