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Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids
npj Aging ( IF 4.1 ) Pub Date : 2016-06-23 , DOI: 10.1038/npjamd.2016.12
Antonio Currais , Oswald Quehenberger , Aaron M Armando , Daniel Daugherty , Pam Maher , David Schubert

The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood. We use a proteotoxicity model based upon the inducible expression of Aβ in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Aβ. It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell's demise. Aβ induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death. Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective. Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Aβ, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors.



中文翻译:

淀粉样蛋白毒性引发被大麻素阻断的炎症反应

大脑中的 β 淀粉样蛋白 (Aβ) 和其他聚集蛋白随着年龄的增长而增加,并且经常在神经元中发现。然而,细胞内淀粉样蛋白、衰老和神经变性之间的机制关系尚不清楚。我们使用基于 Aβ 在人类中枢神经系统神经细胞系中可诱导表达的蛋白毒性模型来表征由细胞内 Aβ 引起的不同形式的神经细胞死亡。结果表明,细胞内 Aβ 引发了导致细胞死亡的毒性炎症反应。Aβ 诱导多种促炎基因的表达和花生四烯酸和类花生酸的增加,包括具有神经保护作用的前列腺素和增强死亡的白三烯。四氢大麻酚等大麻素会刺激神经元内 Aβ 的去除,阻断炎症反应,并具有保护作用。总之,这些数据表明,细胞内 Aβ 的积累导致神经细胞内存在复杂且可能的自催化炎症反应,并且这种早期形式的蛋白质毒性可以通过大麻素受体的激活来阻断。

更新日期:2016-06-23
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