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Cell Death Differ. 2015 Oct;22(10):1676-86. doi: 10.1038/cdd.2015.16. Epub 2015 Mar 6.

Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation.

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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.
Department of Genetics, 120 Mason Farm Road 5000 D, Genetic Medicine Building CB#7264 UNC-Chapel Hill, Chapel Hill, NC 27599-7264, USA.
Massachusetts General Hospital, Mass General Institute for Neurodegeneration, 114 16th Street, Charlestown, MA 2129, USA.
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202-5120, USA.


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.

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