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Background  An association between neuroinflammation and age-related neurologic disorders has been established but the molecular mechanisms and cell types involved have not been thoroughly characterized. Activity of the proinflammatory NLRP3 inflammasome is implicated in Alzheimer’s and Parkinson’s disease and our recent studies in patients suggest that dopaminergic neurons within the degenerating mesencephalon express NLRP3 throughout the progression of PD. Here, we directly test the impact of enhanced inflammasome activity in mesencephalic neurons by characterizing motor function, tissue integrity, and neuroinflammation in aging mice harboring hyperactivating mutations within the endogenous murine  Nlrp3  locus, enabled only in cells expressing the dopaminergic neuron-specific  Slc6a3  promoter.    Methods  We compared mice harboring inducible alleles encoding the cryopyrin-associated periodic syndrome activating mutations  Nlrp3   A350V   and  Nlrp3   L351P   inserted into the endogenous mouse  Nlrp3  locus. Tissue specific expression was driven by breeding these animals with mice expressing Cre recombinase under the control of the dopaminergic neuron-specific  Slc6a3  promoter. The experimental mice, designed to express hyperactive NLRP3 only when the endogenous mouse  Nlrp3  promotor is active in dopaminergic neurons, were analyzed throughout 18 months of aging using longitudinal motor function assessments. Biochemical and histologic analyses of mesencephalic tissues were conducted in 1- and 18-month-old animals.    Results  We observed progressive and significant deficits in motor function in animals expressing  Nlrp3   L351P  , compared with animals expressing  Nlrp3   WT   and  Nlrp3   A350V  . Age-dependent neuroinflammatory changes in the mesencephalon were noted in all animals. Analysis of GFAP-immunoreactive astrocytes in the substantia nigra revealed a significant increase in astrocyte number in animals expressing  Nlrp3   L351P   compared with  Nlrp3   WT   and  Nlrp3   A350V  . Further analysis of  Nlrp3   L351P   striatal tissues indicated genotype specific gliosis, elevated  Il1b  expression, and both morphologic and gene expression indicators of proinflammatory A1 astrocytes.    Conclusions  Dopaminergic neurons have the potential to accumulate NLRP3 inflammasome activators with age, including reactive oxygen species, dopamine metabolites, and misfolded proteins. Results indicate the  Nlrp3  locus is active in dopaminergic neurons in aging mice, and that the hyperactive  Nlrp3   L351P   allele can drive neuroinflammatory changes in association with progressive behavioral deficits. Findings suggest neuronal NLRP3 inflammasome activity may contribute to neuroinflammation observed during normal aging and the progression of neurologic disorders.

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice