Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation.
Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1(-/-) and Casp1(-/-) mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-β-mediated neuroinflammation and Casp6-mediated axonal degeneration.
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T1E2, Canada.|Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
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Kaushal
Department of Genetics, 120 Mason Farm Road 5000 D, Genetic Medicine Building CB#7264 UNC-Chapel Hill, Chapel Hill, NC 27599-7264, USA.
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Dye
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T1E2, Canada.|Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
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Pakavathkumar
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T1E2, Canada.|Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
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Foveau
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T1E2, Canada.|Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
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Flores
Massachusetts General Hospital, Mass General Institute for Neurodegeneration, 114 16th Street, Charlestown, MA 2129, USA.
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Hyman
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202-5120, USA.
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Ghetti
Department of Genetics, 120 Mason Farm Road 5000 D, Genetic Medicine Building CB#7264 UNC-Chapel Hill, Chapel Hill, NC 27599-7264, USA.
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Koller
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T1E2, Canada.|Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
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LeBlanc
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001369:Axons / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D053178:Caspase 6 / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D000070576:NLR Proteins; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D053178:Caspase 6; D020170:Caspase 1