NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice
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Open Access
- 19 December 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 493 (7434), 674-678
- https://doi.org/10.1038/nature11729
Abstract
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.Keywords
This publication has 30 references indexed in Scilit:
- Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrineProceedings of the National Academy of Sciences of the United States of America, 2010
- α‐secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generationJournal of Neurochemistry, 2009
- Immune Activation in Brain Aging and Neurodegeneration: Too Much or Too Little?Neuron, 2009
- The Inflammasomes: Guardians of the BodyAnnual Review of Immunology, 2009
- The NALP3 inflammasome is involved in the innate immune response to amyloid-βNature Immunology, 2008
- Amyloid β-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysinCellular and Molecular Life Sciences, 2008
- Chronic Interleukin-1β Expression in Mouse Brain Leads to Leukocyte Infiltration and Neutrophil-Independent Blood–Brain Barrier Permeability without Overt NeurodegenerationJournal of Neuroscience, 2007
- Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathologyJCI Insight, 2007
- Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like diseaseNature Medicine, 2007
- Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory'Nature Protocols, 2006