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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Axons / metabolism
  • Caspase 1 / metabolism*
  • Caspase 6 / metabolism*
  • Cells, Cultured
  • Humans
  • Inflammasomes / metabolism*
  • Inflammation
  • Interleukin-1beta / biosynthesis*
  • Male
  • Mice
  • Neurons / metabolism*
  • Neurons / physiology
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • Apoptosis Regulatory Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLRP1 protein, human
  • Caspase 6
  • Caspase 1