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The deposition of ␤-amyloid in the brain is the key pathogenetic event in Alzheimer's disease. Among the various mechanisms proposed to explain the neurotoxicity of ␤-amyloid deposits, a new one, recently identified in our and other laboratories, suggests that ␤-amyloid is indirectly neurotoxic by activating microglia to produce toxic inflammatory mediators such as cytokines, nitric oxide, and oxygen free radicals. Three findings presented here support this mechanism, showing that ␤-amyloid peptides (25-35), (1-39), and (1-42) activated the classical NADPH oxidase in rat primary culture of microglial cells and human phagocytes: 1) The exposure of the cells to ␤-amyloid peptides stimulates the production of reactive oxygen intermediates; 2) the stimulation is associated with the assembly of the cytosolic components of NADPH oxidase on the plasma membrane, the process that corresponds to the activation of the enzyme; 3) neutrophils and monocytes of chronic granulomatous disease patients do not respond to ␤-amyloid peptides with the stimulation of reactive oxygen intermediate production. Data are also presented that the activation of NADPH oxidase requires that ␤-amyloid peptides be in fibrillary state, is inhibited by inhibitors of tyrosine kinases or phosphatidylinositol 3-kinase and by dibutyryl cyclic AMP, and is potentiated by interferon-␥ or tumor necrosis factor-␣.The most common form of senile dementia, Alzheimer's disease (AD), 1 is characterized by a progressive loss of neurons from particular regions of the brain, by the formation of neurofibrillary tangles in neurons, and by numerous senile plaques in affected brain regions. The major component of the senile plaques is the ␤-amyloid protein (A␤), a 39 -43-amino acid peptide, derived from a larger transmembrane glycoprotein called ␤-amyloid precursor protein (1). The A␤ of the senile plaques consists of fibrils that are 4 -10 nm in diameter and exhibit green birefringence under polarized illumination when stained with Congo Red. According to spectroscopic and x-ray diffraction studies, the amyloid fibril assembly is correlated with the adoption of a ␤-sheet structure (2, 3).According to the "␤-amyloid cascade'' hypothesis, the excessive deposition of A␤ is the key pathogenetic event in AD (4 -8) and would be responsible for neurodegenerative changes of neurons. In the plaques the central deposit of extracellular amyloid fibrils (the core) is surrounded by dystrophic neurites (dendrites and axon terminals) and by activated microglia and reactive astrocytes (9, 10). Furthermore, it has been demonstrated that A␤ is neurotoxic in vitro (7,11,12) and that this toxicity correlates with ␤-sheet structure and fibrillary state (Ref. 13; Ref. 7 and references therein). Data have been also provided showing that it is the amphiphilic nature of the peptides rather than their ␤ structure per se that causes toxicity (14).Studies of A␤ cytotoxicity have resulted in some broad concepts of mechanism that are not mutually exclusive (7,15). One proposes that A␤ can directl...

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A comparative study of the molecular mechanism of interleukin‐6 (IL‐6) gene induction on two breast‐carcinoma‐derived cell lines has been performed. MDA‐MB‐231 cells produce constitutive detectable levels of both secreted 1L‐6 and mRNA which, as expected. are dramatically enhanced following induction by either IL‐1β or tumor necrosis factor‐α (TNF‐α). The levels of both secreted IL‐6 and IL‐6 mRNA are significantly higher in response to IL‐1β in spite of the fact that stimulation by TNF‐α alone enhances the half life of IL‐6 mRNA. The protein synthesis inhibitor cycloheximide is also a fairly strong inducer of IL‐6 in these cells. In contrast, MCF‐7 cells fail to produce detectable IL‐6 protein or mRNA, even after stimulation with proper inducers. Analysis of transcription factors NF‐κB, NFIL6 and NFIL6β, which have been described to be sufficient to activate the IL‐6 gene in other cell systems, shows a similar pattern of expression in both MCF‐7 and MDA‐MB‐231 cells. Furthermore, transfection of a recombinant plasmid carrying the IL‐6 promoter linked to a luciferase reporter gene shows that both cell lines are able to drive IL‐1β or TNF‐α activation of this construction in a very similar manner. Finally, when MCF‐7 cells were treated with IL‐1β or TNF‐α in the presence of cycloheximide, transcription of IL‐6 mRNA from the endogenous IL‐6 gene was observed. These data suggest that a mechanism of IL‐6 gene repression is active in MCF‐7 cells.

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