Garção Pedro, Oliveira Catarina R, Agostinho Paula
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
J Neurosci Res. 2006 Jul;84(1):182-93. doi: 10.1002/jnr.20870.
The inflammatory responses in Alzheimer's disease (AD) and prion-related encephalopathies (PRE) are dominated by microglia activation. Several studies have reported that the amyloid-beta (Abeta) peptides, which are associated with AD, and the pathogenic isoform of prion protein (PrPSc) have a crucial role in neuronal death and gliosis that occur in both of these disorders. In this study, we investigate whether Abeta and PrPSc cause microglia activation per se and whether these amyloidogenic peptides differentially affect these immunoeffector cells. In addition, we also determined whether substances released by Abeta- and PrP-activated microglia induce neuronal death. Cultures of rat brain microglia cells were treated with the synthetic peptides Abeta1-40, Abeta1-42 and PrP106-126 for different time periods. The lipopolysaccharide was used as a positive control of microglia activation. Our results show that Abeta1-40 and PrP106-126 caused similar morphological changes in microglia and increased the production of nitric oxide and hydroperoxides. An increase on inducible nitric oxide synthase expression was also observed in microglia treated with Abeta1-40 or PrP106. However, these peptides affected in a different manner the secretion of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) secretion. In cocultures of microglia-neurons, it was observed that microglia treated with Abeta1-40 or PrP106-126 induced a comparable extent of neuronal death. The neutralizing antibody for IL-6 significantly reduced the neuronal death induced by Abeta- or PrP-activated microglia. Taken together, the data indicate that Abeta and PrP peptides caused microglia activation and differentially affected cytokine secretion. The IL-6 released by reactive microglia caused neuronal injury.
阿尔茨海默病（AD）和朊病毒相关脑病（PRE）中的炎症反应主要由小胶质细胞激活主导。多项研究报告称，与AD相关的β-淀粉样蛋白（Aβ）肽以及朊病毒蛋白的致病异构体（PrPSc）在这两种疾病中发生的神经元死亡和胶质细胞增生中起关键作用。在本研究中，我们调查了Aβ和PrPSc本身是否会导致小胶质细胞激活，以及这些淀粉样生成肽是否会对这些免疫效应细胞产生不同影响。此外，我们还确定了由Aβ和PrP激活的小胶质细胞释放的物质是否会诱导神经元死亡。用合成肽Aβ1-40、Aβ1-42和PrP106-126对大鼠脑小胶质细胞培养物进行不同时间段的处理。脂多糖用作小胶质细胞激活的阳性对照。我们的结果表明，Aβ1-40和PrP106-126在小胶质细胞中引起了相似的形态变化，并增加了一氧化氮和氢过氧化物的产生。在用Aβ1-40或PrP106处理的小胶质细胞中也观察到诱导型一氧化氮合酶表达增加。然而，这些肽对白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）分泌的影响方式不同。在小胶质细胞-神经元共培养中，观察到用Aβ1-40或PrP106-126处理的小胶质细胞诱导了相当程度的神经元死亡。IL-6的中和抗体显著降低了由Aβ或PrP激活的小胶质细胞诱导的神经元死亡。综上所述，数据表明Aβ和PrP肽导致小胶质细胞激活并对细胞因子分泌产生不同影响。反应性小胶质细胞释放的IL-6导致神经元损伤。
