Publication Date:
2012-12-21
Description:
Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-beta peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-beta activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1beta 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-1beta activation as well as enhanced amyloid-beta clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-beta 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812809/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heneka, Michael T -- Kummer, Markus P -- Stutz, Andrea -- Delekate, Andrea -- Schwartz, Stephanie -- Vieira-Saecker, Ana -- Griep, Angelika -- Axt, Daisy -- Remus, Anita -- Tzeng, Te-Chen -- Gelpi, Ellen -- Halle, Annett -- Korte, Martin -- Latz, Eicke -- Golenbock, Douglas T -- R01 AI083713/AI/NIAID NIH HHS/ -- R01 GM054060/GM/NIGMS NIH HHS/ -- R01 HL093262/HL/NHLBI NIH HHS/ -- U19 AI084048/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jan 31;493(7434):674-8. doi: 10.1038/nature11729. Epub 2012 Dec 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. michael.Heneka@ukb.uni-bonn.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23254930" target="_blank"〉PubMed〈/a〉
Keywords:
Aged
;
Aged, 80 and over
;
Alzheimer Disease/enzymology/genetics/*pathology
;
Amyloid beta-Peptides/metabolism
;
Animals
;
Behavior, Animal
;
Brain/enzymology/*pathology
;
Carrier Proteins/genetics/*metabolism
;
Caspase 1/genetics/metabolism
;
Gene Expression Regulation, Enzymologic
;
Humans
;
Inflammasomes/metabolism
;
Interleukin-1beta/metabolism
;
Memory
;
Mice
;
Mice, Inbred C57BL
;
Mice, Transgenic
;
Mild Cognitive Impairment/enzymology/physiopathology
;
Nitric Oxide Synthase Type II/metabolism
;
Phagocytosis/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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