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.
Halle
Annett
A
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Hornung
Veit
V
Petzold
Gabor C
GC
Stewart
Cameron R
CR
Monks
Brian G
BG
Reinheckel
Thomas
T
Fitzgerald
Katherine A
KA
Latz
Eicke
E
Moore
Kathryn J
KJ
Golenbock
Douglas T
DT
D000544:Alzheimer Disease / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human