NLRP3 inflammasome activation drives tau pathology

Nature, 2019

The NLRP3 inflammasome links two major components of Alzheimer’s desease: amyloid-β and tau protein, as recently reported by scientists from German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn. Amyloid-β plaques can activate the NLRP3 inflammasome which in return can result in additional amyloid-β deposits. On the other hand, NLRP3 inflammasome phosphorylates tau, resulting in tau aggregates within neurons. This ambilateral impact of NLRP3 inflammasome in the pathogenesis of tauopathies has been described by Christina Ising and colleagues in an article titled “NLRP3 inflammasome activation drives tau pathology” appeared November 20 in Nature.

 

Abstract

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.

Products used in this work: GTX74034

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