NLRP3 is activated in Alzheimer´s disease and contributes to pathology in APP/PS1 mice
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 Gelpi,Annett Halle,Martin Korte,Eicke Latz,Eicke Latz,Douglas T. Golenbock +15 more
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TLDR
The role of the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease was investigated in this article, which showed an important role for the inflammasome.Abstract:
Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. 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.read more
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Journal ArticleDOI
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
Inflammasomes: mechanism of action, role in disease, and therapeutics
TL;DR: Increasing evidence in mouse models strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases.
Journal ArticleDOI
Mechanisms and Functions of Inflammasomes
Mohamed Lamkanfi,Vishva M. Dixit +1 more
TL;DR: This Review summarizes recent insights into inflammasome biology and discusses the questions that remain in the field.
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Immune attack: the role of inflammation in Alzheimer disease
TL;DR: As inflammation in AD primarily concerns the innate immune system — unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides — the concept of neuroinflammation in AD may need refinement.
Journal ArticleDOI
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.
Justin M. Long,David M. Holtzman +1 more
TL;DR: Recent advances in the understanding of AD pathobiology are reviewed and current treatment strategies are discussed, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies.
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Annett Halle,Veit Hornung,Gabor C. Petzold,Cameron R. Stewart,Brian G. Monks,Thomas Reinheckel,Katherine A. Fitzgerald,Eicke Latz,Kathryn J. Moore,Douglas T. Golenbock +9 more
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