The NALP3 inflammasome is involved in the innate immune response to amyloid-β

Abstract

The fibrillar peptide amyloid-β (Aβ) has a chief function in the pathogenesis of Alzheimer's disease. Interleukin 1β (IL-1β) is a key cytokine in the inflammatory response to Aβ. Insoluble materials such as crystals activate the inflammasome formed by the cytoplasmic receptor NALP3, which results in the release of IL-1β. Here we identify the NALP3 inflammasome as a sensor of Aβ in a process involving the phagocytosis of Aβ and subsequent lysosomal damage and release of cathepsin B. Furthermore, the IL-1β pathway was essential for the microglial synthesis of proinflammatory and neurotoxic factors, and the inflammasome, caspase-1 and IL-1β were critical for the recruitment of microglia to exogenous Aβ in the brain. Our findings suggest that activation of the NALP3 inflammasome is important for inflammation and tissue damage in Alzheimer's disease.

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Figure 1: Fibrillar Aβ induces the caspase-1-dependent release of interleukin-1β.
Figure 2: Fibrillar Aβ activates the NALP3 inflammasome.
Figure 3: Phagocytosis of Aβ is necessary for IL-1β release and induces lysosomal damage.
Figure 4: Lysosomal damage triggers the release of cathepsin B, which is involved in the IL-1β pathway.
Figure 5: Aβ-induced expression of proinflammatory and chemotactic factors is mediated by caspase-1 activation in microglia.
Figure 6: IL-1-mediated pathways contribute to microglial activation induced by Aβ in vivo.

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Acknowledgements

MyD88-deficient mice were provided by S. Akira (University of Osaka) and caspase-1-deficient mice were provided by A. Hise (Case Western Reserve University). We thank A. Cerny and J. Boulanger for animal husbandry and care, and K. Wozniak and S. Zhou for advice. Supported by the German Academic Exchange Office (A.H.), a European Union Marie Curie Fellowship (G.C.P.), the German Science Foundation (V.H.) and the US National Institutes of Health (GM54060 and AI065483 to D.T.G. and E.L.; AG20255 to K.J.M.).

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Correspondence to Douglas T Golenbock.

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Halle, A., Hornung, V., Petzold, G. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9, 857–865 (2008). https://doi.org/10.1038/ni.1636

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