Kaushal, V.Dye, R.Pakavathkumar, P.Foveau, B.Flores, J.Hyman, B.Ghetti, B.Koller, B. H.LeBlanc, A. C.2016-12-152016-12-152015-10Kaushal, V., Dye, R., Pakavathkumar, P., Foveau, B., Flores, J., Hyman, B., … LeBlanc, A. C. (2015). Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death and Differentiation, 22(10), 1676–1686. https://doi.org/10.1038/cdd.2015.161350-9047 1476-5403https://hdl.handle.net/1805/11622Neuronal 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 increaseden-USPublisher's PolicyProteinsAlzheimer DiseaseArticle