Journal ArticleDOI
Caspase signalling controls microglia activation and neurotoxicity
Miguel Angel Burguillos,Tomas Deierborg,Edel Kavanagh,Annette Persson,Nabil Hajji,Nabil Hajji,Albert García-Quintanilla,Josefina Cano,Patrik Brundin,Elisabet Englund,José L. Venero,Bertrand Joseph +11 more
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TLDR
Inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves, as shown in the case of Parkinson’s disease and AD.Abstract:
Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-d-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson’s disease (PD) and the frontal cortex of individuals with Alzheimer’s disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves. Numerous in vivo clinical imaging and neuropathology studies suggest that activated microglia, the resident immune cells of the central nervous system, play prominent roles in the pathogenesis of neurodegenerative disorders, including PD, multiple sclerosis and AD 1,2 . Microglia are necessary for normal brain function; however, uncontrolled and over-activated microglia can trigger neurotoxicity. They are a prominent source of pro-inflammatory factors and oxidative stress such as tumour-necrosis factor (TNF)-a, nitric oxide and interleukin (IL)-1b, which are neurotoxic 2,3 . Toll-like receptors (TLRs) are a family of pattern-recognition receptors in the innate immune system. Exogenous and endogenous TLR ligands activate microglia 1 . Intracerebral delivery of lipopolysaccharide (LPS), the major component of Gram-negative bacterial walls and a ligand for TLR4, leads in vivo to microglia activation and neuronal injury, and is used as model for brain inflammation 4,5 . Synergistic effects between interferon-c (IFN-c) and several TLR ligands (including TLR4) have been suggested, suggesting crosstalk between these pro-inflammatory receptor signalling pathways 6 . Furthermore, IFN-c receptor-deficient mice are less susceptible to LPS-induced endotoxic shock than control mice 7 . Finally, TLR4 has been implicated in AD pathophysiology in several contexts. Thus, the upregulation of cytokines is TLR4 dependent in an AD mouse model 8 ; certain TLR4 single nucleotide polymorphisms are associated with increased risk for AD 9 ; the levels of TLR4 messenger RNA (mRNA) are upregulated in APP transgenic mice 10 ; and increased TLR4 expression is associated with amyloid plaque deposition in AD brain tissue 10 . Caspases, a family of cysteinyl-aspartate-specific proteases, are executioners of apoptotic cell death and their activation is considered a commitment to cell death 11,12 . Certain caspases, for example caspase-1, also play a pivotal role in immune-mediated inflammation. In this situation, caspase activation is associated with the maturation of pro-inflammatory cytokines, such as IL-1b, IL-18, IL-33, and not with apoptosis 13 . Inhibition of caspase activation protects against neuronal loss in several animal models of brain diseases involving activated microglia, including hypoxic ischaemia/stroke, acute bacterial meningitis, brain trauma and 6-hydroxydopamine and 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonism models 2,14–17 . Currently, it is unclear whether inhibition of caspase activation specifically in microglia contributes to the neuroprotective effects of caspase inhibitors. We have now discovered that microglial activation in cell and animal models of inflammation involves caspases and that inhibition of the cascade in microglia prevents neurodegeneration. Furthermore, we demonstrate that caspase activation occurs in microglia in the brains of individuals with PD and AD, and thereby we validate the observations we made in relevant cell and animal models.read more
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Neuroinflammation in Alzheimer's disease
Michael T. Heneka,Monica J. Carson,Joseph El Khoury,Gary E. Landreth,Frederic Brosseron,Douglas L. Feinstein,Andreas H. Jacobs,Tony Wyss-Coray,Tony Wyss-Coray,Javier Vitorica,Richard M. Ransohoff,Karl Herrup,Sally A. Frautschy,Bente Finsen,Guy C. Brown,Alexei Verkhratsky,Alexei Verkhratsky,Alexei Verkhratsky,Koji Yamanaka,Jari Koistinaho,Eicke Latz,Eicke Latz,Annett Halle,Gabor C. Petzold,Terrence Town,Dave Morgan,Mari L. Shinohara,V. Hugh Perry,Clive Holmes,Clive Holmes,Nicolas G. Bazan,David J. Brooks,Stéphane Hunot,Bertrand Joseph,Nikolaus Deigendesch,Olga Garaschuk,Erik Boddeke,Charles A. Dinarello,John C.S. Breitner,Greg M. Cole,Douglas T. Golenbock,Markus P. Kummer +41 more
TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.
Journal ArticleDOI
Reactive Astrocytes: Production, Function, and Therapeutic Potential
Shane A. Liddelow,Ben A. Barres +1 more
TL;DR: Recent studies that demonstrate that different initiating CNS injuries can elicit at least two types of "reactive" astrocytes with strikingly different properties, one type being helpful and the other harmful are summarized.
Journal ArticleDOI
Neuroinflammation in Alzheimer's disease: Current evidence and future directions
Valeria Calsolaro,Paul Edison +1 more
TL;DR: This review focuses on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro‐inflammatory factors, and neuronal damage, and the relevance of inflammation as a diagnostic and therapeutic target.
Journal ArticleDOI
Microglial cell origin and phenotypes in health and disease.
Kaoru Saijo,Christopher K. Glass +1 more
TL;DR: Recent studies that provide new insights into the origin and phenotypes of microglia in health and disease are discussed.
Journal ArticleDOI
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Lorenzo Galluzzi,J M Bravo-San Pedro,Ilio Vitale,Stuart A. Aaronson,John M. Abrams,Dieter Adam,Emad S. Alnemri,Lucia Altucci,David W. Andrews,Margherita Annicchiarico-Petruzzelli,Eric H. Baehrecke,Nicolas G. Bazan,Mathieu J.M. Bertrand,Mathieu J.M. Bertrand,Katiuscia Bianchi,Katiuscia Bianchi,Mikhail V. Blagosklonny,Klas Blomgren,Christoph Borner,Dale E. Bredesen,Dale E. Bredesen,Catherine Brenner,Catherine Brenner,Michelangelo Campanella,Eleonora Candi,Francesco Cecconi,Francis Ka-Ming Chan,Navdeep S. Chandel,Emily H. Cheng,Jerry E. Chipuk,John A. Cidlowski,Aaron Ciechanover,Ted M. Dawson,Valina L. Dawson,V De Laurenzi,R De Maria,Klaus-Michael Debatin,N. Di Daniele,Vishva M. Dixit,Brian David Dynlacht,Wafik S. El-Deiry,Gian Maria Fimia,Richard A. Flavell,Simone Fulda,Carmen Garrido,Marie-Lise Gougeon,Douglas R. Green,Hinrich Gronemeyer,György Hajnóczky,J M Hardwick,Michael O. Hengartner,Hidenori Ichijo,Bertrand Joseph,Philipp J. Jost,Thomas Kaufmann,Oliver Kepp,Daniel J. Klionsky,Richard A. Knight,Richard A. Knight,Sharad Kumar,Sharad Kumar,John J. Lemasters,Beth Levine,Beth Levine,Andreas Linkermann,Stuart A. Lipton,Richard A. Lockshin,Carlos López-Otín,Enrico Lugli,Frank Madeo,Walter Malorni,Jean-Christophe Marine,Seamus J. Martin,J-C Martinou,Jan Paul Medema,Pascal Meier,Sonia Melino,Noboru Mizushima,Ute M. Moll,Cristina Muñoz-Pinedo,Gabriel Núñez,Andrew Oberst,Theocharis Panaretakis,Josef M. Penninger,Marcus E. Peter,Mauro Piacentini,Paolo Pinton,Jochen H. M. Prehn,Hamsa Puthalakath,Gabriel A. Rabinovich,Kodi S. Ravichandran,Rosario Rizzuto,Cecília M. P. Rodrigues,David C. Rubinsztein,Thomas Rudel,Yufang Shi,Hans-Uwe Simon,Brent R. Stockwell,Brent R. Stockwell,Gyorgy Szabadkai,Gyorgy Szabadkai,Stephen W.G. Tait,H. L. Tang,Nektarios Tavernarakis,Nektarios Tavernarakis,Yoshihide Tsujimoto,T Vanden Berghe,T Vanden Berghe,Peter Vandenabeele,Peter Vandenabeele,Andreas Villunger,Erwin F. Wagner,Henning Walczak,Eileen White,W. G. Wood,Junying Yuan,Zahra Zakeri,Boris Zhivotovsky,Boris Zhivotovsky,Gerry Melino,Gerry Melino,Guido Kroemer +121 more
TL;DR: The Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
References
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Journal ArticleDOI
Caspases: the executioners of apoptosis
TL;DR: The importance of caspase prodomains in the regulation of apoptosis is further highlighted by the recognition of adapter molecules, such as RAIDD [receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain]/CRADD (caspase and RIP adapter with death domain), which binds to the prodomain of cspase-2 and recruits it to the signalling complex.
Journal ArticleDOI
Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis
Donald W. Nicholson,Ambereen Ali,Nancy A. Thornberry,John P. Vaillancourt,C K Ding,Michel Gallant,Yves Gareau,Patrick R. Griffin,Marc Labelle,Yuri Lazebnik +9 more
TL;DR: A potent peptide aldehyde inhibitor has been developed and shown to prevent apoptotic events in vitro, suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.
Journal ArticleDOI
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
TL;DR: Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.
Journal ArticleDOI
Microglia: active sensor and versatile effector cells in the normal and pathologic brain
TL;DR: This review focuses on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.
Journal ArticleDOI
Signaling to NF-κB by Toll-like receptors
Taro Kawai,Shizuo Akira +1 more
TL;DR: The role of NF-κB in TLR signaling pathways has been discussed in this article, where the authors review recent progress in their understanding of the role and potential implications for molecular medicine.