title: Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor.
abstract: Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid beta peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1 alpha, IL-1 beta, TNF-alpha and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-gamma and IL-6, whereas that of C1-Inh could be stimulated only by IFN-gamma. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1 beta, IL-1 alpha, and TNF-alpha, the amyloid peptide A beta 1-42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.
authors.affiliation: Department of Psychiatry, Graduate School Neurosciences, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Veerhuis
authors.forename: I
authors.initials: I
authors.lastname: Janssen
authors.forename: C J
authors.initials: CJ
authors.lastname: De Groot
authors.forename: F L
authors.initials: FL
authors.lastname: Van Muiswinkel
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: P
authors.initials: P
authors.lastname: Eikelenboom
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001254:Astrocytoma / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003167:Complement Activation; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D015922:Complement C1q / Q000378:metabolism; D015923:Complement C1r / Q000378:metabolism*; D003173:Complement C1s / Q000378:metabolism*; D003176:Complement C3 / Q000378:metabolism*; D003181:Complement C4 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000032:analysis / Q000494:pharmacology*; D015850:Interleukin-6 / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000737:chemistry*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000494:pharmacology*
chemical_list: D003174:Complement C1 Inactivator Proteins; D003176:Complement C3; D003181:Complement C4; D007375:Interleukin-1; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015922:Complement C1q; D007371:Interferon-gamma; D015923:Complement C1r; D003173:Complement C1s