Astroglial Cells : Role in Neurodegenerative-Inflammatory Processes in the Central Nervous System

Sammanfattning: Inflammatory processes, mediated by the pro-inflammatory cytokines interleukin (IL) -1a/b, tumor necrosis factora(TNFa), IL-6 and excitotoxic actions of glutamate, are proposed to be implicated in neurodegenerative diseases, such as Alzheimer's disease.A neurotoxic fragment ofb-amyloid,bA25-35, was shown to induce a reactive phenotype of primary astrocytes and microglial cells in a time-dependent manner. The morphological changes were found to coincide with a transient expression of IL-1band a sustained increased IL-1aand IL-6 expression as determined by reverse transcription and polymerase chain reaction analysis of RNA extracted from treated and untreated cells.bA25-35 induced cytokine expression in astroglial cells from IL-1 receptor type I (IL-1RI)-deficient cultures, showed a hypersensitive IL-1aresponse and a decreased IL-6 response. Thus it was concluded that the IL-1RI is necessary for full scale induction of IL-6. Expression of IL-6 and TNFain the absence of a signalling IL-1 receptor may be induced by reactive oxygen species and/or by activation of NFkB. The IL-1aincrease may reflect a missing transcriptional feed-back regulation involving the IL-1RI.The role of IL-1 receptor accessory protein (IL-1RAcP) in IL-1binduced signalling was investigated in astroglial cultures from IL-1RAcP deficient mice. IL-1bhad no effect on nuclear NFkB binding activity suggesting that IL-1RAcP is necessary for NFkB activation. By use of specific antibodies it was shown that the activated NFkB complex consisted of p50 and possibly p52 or RelB, NFkB related proteins, respectively.The excitatory amino acid glutamate was shown to stimulate respiratory activity in primary astroglial cell cultures. This effect was found to be correlated to the Na+-dependent high affinity glutamate uptake and an increased Na+/K+-ATPase activity since it could be blocked by ouabain and mimiced by gramicidin.Carbon tetrachloride (CCl4) and n-hexane, two neurotoxic organic solvents, were shown to interfere with cAMP formation in primary rat astroglial cells. In addition, both solvents decreased basal and glutamate induced increase in respiratory activity an observation which may reflect both a decreased Na+/K+-ATPase activity and a reduction of high-affinity glutamate uptake.