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

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          Abstract

          Alzheimer´s Disease (AD) is the world’s most common dementing illness. Deposition of amyloid beta peptide (Aβ) drives cerebral neuroinflammation by activating microglia 1, 2 . Indeed, Aβ activation of the NLRP3 inflammasome in microglia is fundamental for IL-1β maturation and subsequent inflammatory events 3 . However, it remains unknown whether NLRP3 activation contributes to AD in vivo. Here, we demonstrate strongly enhanced active caspase-1 expression in human MCI and AD brains suggesting a role for the inflammasome in this neurodegenerative disease. NLRP3 −/− or caspase-1 −/− mice carrying mutations associated with familiar AD were largely protected from loss of spatial memory and other AD-associated sequelae and demonstrated reduced brain caspase-1 and IL-1β activation as well as enhanced Aβ clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of Aβ in the APP/PS1 model of Alzheimer’s disease. These results reveal an important role for the NLRP3 / caspase-1 axis in AD pathogenesis, and suggest that NLRP3 inflammasome inhibition represents a novel therapeutic intervention for AD.

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          Most cited references 33

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          A synaptic model of memory: long-term potentiation in the hippocampus.

          Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.
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            The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.

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

              The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1beta and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                30 April 2013
                19 December 2012
                31 January 2013
                30 October 2013
                : 493
                : 7434
                Affiliations
                [1 ]Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
                [2 ]Institute of Innate Immunity, University of Bonn, Bonn, Germany
                [3 ]Deutsches Zentrum f�r Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
                [4 ]Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, 38106 Braunschweig, Germany
                [5 ]Department of Medicine and Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
                [6 ]Neurological Tissue Bank, University of Barcelona-Hospital Clinic, IDIBAPS, Barcelona, Spain
                [7 ]Center for Advanced European Studies and Research-CAESAR, Bonn, Germany
                Author notes
                [# ]Correspondence and requests for materials should be addressed to E.L. ( eicke.latz@ 123456uni-bonn.de ), M.T.H. ( michael.Heneka@ 123456ukb.uni-bonn.de ) or D.G. ( douglas.golenbock@ 123456umassmed.edu )
                [*]

                These authors contributed equally to this work

                Article
                NIHMS418619
                10.1038/nature11729
                3812809
                23254930

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: U19 AI084048 || AI
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL093262 || HL
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM054060 || GM
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI083713 || AI
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