Gitter B D, Cox L M, Rydel R E, May P C
Central Nervous System Research Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10738-41. doi: 10.1073/pnas.92.23.10738.
Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven in part by the deposition of amyloid beta (A beta), a 39- to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Recent descriptions of in vitro neurotoxic effects of A beta support this hypothesis and suggest toxicity might be mediated by A beta-induced neuronal calcium disregulation. In addition, it has been reported that "aging" A beta results in increased toxic potency due to peptide aggregation and formation of a beta-sheet secondary structure. In addition, A beta might also promote neuropathology indirectly by activating immune/inflammatory pathways in affected areas of the brain (e.g., cortex and hippocampus). Here we report that A beta can modulate cytokine secretion [interleukins 6 and 8 (IL-6 and IL-8)] from human astrocytoma cells (U-373 MG). Freshly prepared and aged A beta modestly stimulated IL-6 and IL-8 secretion from U-373 MG cells. However, in the presence of interleukin-1 beta (IL-1 beta), aged, but not fresh, A beta markedly potentiated (3- to 8-fold) cytokine release. In contrast, aged A beta did not potentiate substance P (NK-1)- or histamine (H1)-stimulated cytokine production. Further studies showed that IL-1 beta-induced cytokine release was potentiated by A beta-(25-35), while A beta-(1-16) was inactive. Calcium disregulation may be responsible for the effects of A beta on cytokine production, since the calcium ionophore A23187 similarly potentiated IL-1 beta-induced cytokine secretion and EGTA treatment blocked either A beta or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain regions may be mediated in part by the ability of A beta to exacerbate inflammatory pathways in a conformation-dependent manner.
阿尔茨海默病（AD）中的神经退行性过程被认为部分是由β-淀粉样蛋白（Aβ）的沉积所驱动，Aβ是淀粉样前体蛋白经选择性切割产生的一种由39至43个氨基酸组成的肽产物。最近关于Aβ体外神经毒性作用的描述支持了这一假说，并表明毒性可能由Aβ诱导的神经元钙调节紊乱介导。此外，据报道，“老化”的Aβ由于肽聚集和β-折叠二级结构的形成，其毒性效力增加。此外，Aβ还可能通过激活大脑受影响区域（如皮质和海马体）的免疫/炎症途径间接促进神经病理学发展。在此我们报告，Aβ可调节人星形细胞瘤细胞（U-373 MG）的细胞因子分泌[白细胞介素6和8（IL-6和IL-8）]。新鲜制备的和老化的Aβ适度刺激U-373 MG细胞分泌IL-6和IL-8。然而，在白细胞介素-1β（IL-1β）存在的情况下，老化的而非新鲜的Aβ显著增强（3至8倍）细胞因子释放。相比之下，老化的Aβ并未增强P物质（NK-1）或组胺（H1）刺激的细胞因子产生。进一步研究表明，Aβ-（25-35）增强了IL-1β诱导的细胞因子释放，而Aβ-（1-16）无活性。钙调节紊乱可能是Aβ对细胞因子产生影响的原因，因为钙离子载体A23187同样增强了IL-1β诱导的细胞因子分泌，而EGTA处理可阻断Aβ或A23187的活性。因此，AD受影响脑区的慢性神经退行性变可能部分由Aβ以构象依赖方式加剧炎症途径的能力所介导。
