炎症体
小胶质细胞
神经退行性变
神经炎症
β淀粉样蛋白
化学
τ蛋白
细胞生物学
炎症
葛兰素史克-3
淀粉样蛋白(真菌学)
发病机制
淀粉样前体蛋白
高磷酸化
病理
神经科学
生物
医学
激酶
免疫学
疾病
阿尔茨海默病
作者
Christina Ising,Carmen Venegas,Shuangshuang Zhang,Hannah Scheiblich,Susanne V. Schmidt,Ana Maria Menezes Vieira-Saecker,Stephanie Schwartz,Shadi Albasset,Róisín M. McManus,Darío Tejera,Angelika Griep,Francesco Santarelli,Frederic Brosseron,Sabine Opitz,James Stunden,Maximilian Merten,Rakez Kayed,Douglas T. Golenbock,David Blum,Eicke Latz,Luc Buée,Michael T. Heneka
出处
期刊:Nature
[Springer Nature]
日期:2019-11-20
卷期号:575 (7784): 669-673
被引量:821
标识
DOI:10.1038/s41586-019-1769-z
摘要
Alzheimer’s disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer’s disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation. The authors show that NLRP3 inflammasome is activated in microglia of patients with fronto-temporal dementia and in a mouse model of tau pathology, and that the loss of NLRP3 inflammasome function decreases tau pathology and improves cognition in mice.
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