The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer's disease.
The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer's disease.
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DOI：
10.1186/s13024-016-0088-1
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发表时间：
2016-03-03
影响因子：
15.1
通讯作者：
Clerici M
中科院分区：
文献类型：
--
作者：
Saresella M;La Rosa F;Piancone F;Zoppis M;Marventano I;Calabrese E;Rainone V;Nemni R;Mancuso R;Clerici M
白细胞介素-1 β（IL-1β）及其关键调节因子炎性体被怀疑在阿尔茨海默病（AD）中观察到的神经炎症中发挥作用;然而，在AD患者中没有结论性数据。炎性小体组分（NLRP 1、NLRP 3、PYCARD、半胱天冬酶1、5和8）和下游效应物（IL-1β、IL-18）的mRNA在重度和轻度AD中上调。在单独的重度AD中，共表达NLRP 3与半胱天冬酶1或半胱天冬酶8的单核细胞显著增加，而那些共表达NLRP 1和NLRP 3与PYCARD的单核细胞在重度和轻度AD中均增加。AD中NLRP 1和NLRP 3炎性体的激活通过共聚焦显微镜蛋白共定位和单核细胞产生的促炎细胞因子IL-1β和IL-18的显著更高的量来证实。在MCI中，NLRP 3的表达增加，但PYCARD或半胱天冬酶1的表达没有增加，表明功能性炎性小体在这些个体中没有组装：这通过缺乏共定位和促炎细胞因子产生来证实。至少两种不同炎性小体复合物的激活解释了AD相关的神经炎症。针对炎性小体激活的策略可能有助于AD的治疗。
Interleukin-1 beta (IL-1β) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer’s disease (AD); no conclusive data are nevertheless available in AD patients. mRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1β, IL-18) was up-regulated in severe and MILD AD. Monocytes co-expressing NLRP3 with caspase 1 or caspase 8 were significantly increased in severe AD alone, whereas those co-expressing NLRP1 and NLRP3 with PYCARD were augmented in both severe and MILD AD. Activation of the NLRP1 and NLRP3 inflammasomes in AD was confirmed by confocal microscopy proteins co-localization and by the significantly higher amounts of the pro-inflammatory cytokines IL-1β and IL-18 being produced by monocytes. In MCI, the expression of NLRP3, but not the one of PYCARD or caspase 1 was increased, indicating that functional inflammasomes are not assembled in these individuals: this was confirmed by lack of co-localization and of proinflammatory cytokines production. The activation of at least two different inflammasome complexes explains AD-associated neuroinflammation. Strategies targeting inflammasome activation could be useful in the therapy of AD.