Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer's pathology.
Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer's pathology.
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DOI：
10.1111/j.1582-4934.2008.00496.x
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发表时间：
2008-12
影响因子：
5.3
通讯作者：
Kauppinen A
中科院分区：
文献类型：
--
作者：
Salminen A;Ojala J;Suuronen T;Kaarniranta K;Kauppinen A
遗传学和分子生物学研究已经证实了淀粉样蛋白β的产生和纤维化在阿尔茨海默病（AD）发病机制中的核心作用。然而，从淀粉样蛋白-β肽寡聚化到AD的主要病理学标志（如神经元缠结、炎症和胆碱能神经元损失）的病理学途径在很大程度上是未知的。先天免疫防御系统利用模式识别受体对各种危险和病原体相关的分子结构作出反应。β淀粉样蛋白寡聚体和原纤维及其细胞效应可以激活人脑的先天免疫防御并诱导炎症和凋亡反应。β淀粉样蛋白低聚物可以干扰神经元膜功能的许多方面，并可以引起神经元钾（K+）外流。低K+浓度是NALP 1炎性体的有效激活剂，然后刺激半胱天冬酶-1切割IL-1β和IL-18细胞因子的前体。有趣的是，最近的观察表明，淀粉样蛋白-β原纤维可以通过小鼠小胶质细胞中的溶酶体损伤激活NALP 3炎性体。我们将在此综述NALP炎性小体在神经元和小胶质细胞中的激活机制以及在脑中的几种下游效应，证明毒性淀粉样蛋白-β寡聚体和纤维可以在炎性小体中点燃并诱导阿尔茨海默病病理。
Genetic and molecular studies have confirmed the central role of amyloid-β production and fibrillation in the pathogenesis of Alzheimer's disease (AD). However, the pathological pathways from amyloid-β peptide oligomerization to the major pathological hallmarks of AD, such as neurofibrillary tangles, inflammation and loss of cholinergic neurons, are largely unknown. The innate immunity defence system utilizes pattern recognition receptors to respond to a variety of danger- and pathogen-associated molecular structures. Amyloid-β oligomers and fibrils and their cellular effects can activate the innate immunity defence and induce inflammatory and apoptotic responses in human brain. Amyloid-β oligomers can interfere with many aspects of neuronal membrane functions and can evoke potassium (K+) efflux from neurons. A low K+ concentration is a potent activator for the NALP1 inflammasomes, which then stimulate caspase-1 to cleave the proforms of IL-1β and IL-18 cytokines. Interestingly, recent observations have demonstrated that amyloid-β fibrils can activate NALP3 inflammasomes Via the lysosomal damage in mouse microglia. We will review here the activation mechanisms of NALP inflammasomes in neurons and microglia and several downstream effects in brain demonstrating that toxic amyloid-β oligomers and fibrils can light afire in inflammasomes and induce Alzheimer's pathology.