IPAF inflammasome is involved in interleukin-1β production from astrocytes, induced by palmitate; implications for Alzheimer's Disease.
Inflammatory response has been strongly implicated in the pathogenesis of numerous diseases, including Alzheimer's disease (AD). However, little is known about the molecular mechanisms initiating the generation of inflammatory molecules in the central nervous system, such as interleukin-1β (IL-1β). Previously we identified that palmitate can induce primary astrocytes to produce cytokines, causing AD-like changes in primary neurons. Here we investigated and identified that palmitate induced the activation of ice protease-activating factor (IPAF)-apoptosis-associated speck-like protein containing a caspase activation and recruitment domains (CARD) (ASC) inflammasome in astrocytes leading to the maturation of IL-1β, thereby implicating that not only pathogen-related factors can activate the IPAF-ASC inflammasome. Moreover, downregulating IPAF (which was found to be regulated by cAMP response element-binding protein) in astrocytes through silencing to decrease IL-1β secretion from the astrocytes reduced the generation of amyloid-β42 by primary neurons. Furthermore, the expression levels of IPAF and ASC were found significantly elevated in a subgroup of sporadic AD patients, suggesting an involvement of the IPAF-ASC inflammasome in the inflammatory response associated with AD, and thus could be a potential therapeutic target for AD.
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
Li
L
Liu
Christina
C
Chan
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism* / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C435692:NLRC4 protein, human; D010168:Palmitates; D010446:Peptide Fragments; C538897:amyloid beta-protein (40-42)
Alzheimer's disease; Fatty acid; IL-1β; IPAF; Inflammasome