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NLPR3炎性小体激活引发tau病理形成
2019-11-21 13:07

德国波恩大学医院Michael T. Heneka研究小组取得一项新进展。他们的研究表明,NLRP3炎性小体激活能够促进tau病理形成。相关论文2019年11月20日在线发表在《自然》上

研究人员发现,NLRP3炎性小体功能的丧失通过调节tau激酶和磷酸酶降低了tau过度磷酸化和聚集。Tau激活NLRP3炎性小体,脑内注射含原纤维淀粉样β的脑匀浆以NLRP3依赖性方式诱导tau病理发生。这些数据确定了小胶质细胞和NLRP3炎性小体激活在tau发病机理中的重要作用,并支持阿尔茨海默氏病的淀粉样蛋白级联假说,并且这表明神经纤维缠结在淀粉样蛋白-β诱导的小胶质细胞激活的下游进展。

据了解,阿尔茨海默氏病的特征是斑块中存在淀粉样蛋白β积累,神经原纤维缠结中过度磷酸化的tau聚集和神经发炎,从而共同导致神经变性和认知能力下降。NLRP3炎性小体在激活时在小胶质细胞内部组装,导致caspase-1的切割和活性增加以及下游白介素-1β的释放。尽管已证明NLRP3炎性小体对于小鼠淀粉样β病理学的发展和进展至关重要,但对tau病理学的确切作用仍然未知。

附:英文原文

Title: NLRP3 inflammasome activation drives tau pathology

Author: Christina Ising, Carmen Venegas, Shuangshuang Zhang, Hannah Scheiblich, Susanne V. Schmidt, Ana Vieira-Saecker, Stephanie Schwartz, Shadi Albasset, Risn M. McManus, Dario Tejera, Angelika Griep, Francesco Santarelli, Frederic Brosseron, Sabine Opitz, James Stunden, Maximilian Merten, Rakez Kayed, Douglas T. Golenbock, David Blum, Eicke Latz, Luc Bue, Michael T. Heneka

Issue&Volume: 2019-11-20

Abstract: Alzheimers 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-1 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 Alzheimers 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.

DOI: 10.1038/s41586-019-1769-z

Source: https://www.nature.com/articles/s41586-019-1769-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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