Cytokine Communication Between Neurons and Glia and the Pathogenesis of Alzheimer’s Disease
Brain inflammation is a key feature in the development of Alzheimer’s disease. Numerous inflammatory markers can be observed in afflicted brain regions by immunohistochemical analysis. Epidemiological studies indicate that exposure to anti-inflammatory drugs can delay the onset of this disease. Microglia are likely to have a pivotal role in this inflammatory process since these cells are potent mediators of cerebral inflammation. Microglia have also been found specifically associated with β-amyloid deposits that progress into mature neuritic plaques, structures that are considered to be intimately connected with the pathology and progression of the disease. We have examined β-amyloid-induced inflammatory responses in a murine microglial cell line, BV-2. We have found that exposure of BV-2 cells to exogenous β-amyloid induces secretion of endogenous β-amyloid. Furthermore, β-amyloid exposure results in pro-inflammatory events, such as the translocation of the transcriptional activator, NF-kB, and a 2- to 5-fold induction of IL-1 and IL-6. Exposure of neurons to β-amyloid peptide has been reported to induce release of macrophage-colony stimulating factor (M-CSF). Because microglia are target cells for M-CSF and because M-CSF is found at increased levels in the central nervous system in Alzheimer’s disease, we examined the effects of this cytokine on the inflammatory activation of BV-2 cells. We found that while MCSF and β-amyloid each have modest effects on BV-2 cytokine production, together these two molecules act synergistically to dramatically generate IL-1, IL-6, and nitric oxide. Identical results have been obtained in rat organotypic hippocampal cultures. Each of these molecules has been shown to injure neurons and to activate astrocytes causing further neuronal injury. These results have been used to build a model for a self-amplifying pathological cascade in Alzheimer’s disease involving cytokine communication between neurons, microglia, and astrocytes
KeywordsNitric Oxide Neuritic Plaque Diffuse Deposit Cerebral Inflammation Murine Microglial Cell Line
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