NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice

炎症体 小胶质细胞 神经炎症 发病机制 疾病 半胱氨酸蛋白酶1 阿尔茨海默病 医学 神经科学 淀粉样前体蛋白 炎症 免疫学 淀粉样蛋白(真菌学) 病理 生物
作者
Michael T. Heneka,Markus P. Kummer,Andrea Stutz,Andrea Delekate,Stephanie Schwartz,Ana Vieira‐Saecker,Angelika Griep,Daisy Axt,Anita Remus,Te‐Chen Tzeng,Ellen Gelpí,Annett Halle,Martin Körte,Eicke Latz,Douglas T. Golenbock
出处
期刊:Nature [Springer Nature]
卷期号:493 (7434): 674-678 被引量:2285
标识
DOI:10.1038/nature11729
摘要

Alzheimer’s-prone mice deficient in NLRP3 or caspase-1 fail to develop learning deficits and show reduced neuropathology. Alzheimer's disease is associated with activation of the innate immune system. It is known that amyloid-β can activate the NLRP3 inflammasome in vitro in microglia, and here it is shown that the inflammasome has a critical role in Alzheimer's disease pathology in a mouse model in vivo. In the absence of NLRP3 or caspase-1, amyloidosis and neuropathology in mice is reduced, and cognition and associated electrophysiological parameters improved. Examination of post-mortem human Alzheimer's brains supports the link between NLRP3 and brain inflammation. Taken together, these results suggest that amyloid-β-induced activation of NLRP3 enhances the progression of Alzheimer's disease by mediating a harmful chronic inflammatory tissue post-mortem response, and that agents that block the activity of the NLRP3 inflammasome, or inflammasome-derived cytokines, might slow the progression of Alzheimer's disease. Alzheimer’s disease is the world’s most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia1,2. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events3. However, it remains unknown whether NLRP3 activation contributes to Alzheimer’s disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer’s disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3−/− or Casp1−/− mice carrying mutations associated with familial Alzheimer’s disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer’s disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer’s disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer’s disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.
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