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Investigating markers of NLRP3 inflammasome activation in neurodegenerative diseases
Author(s) -
Tang Hao,
Harte Michael
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.040479
Subject(s) - neuroinflammation , proinflammatory cytokine , inflammasome , neurodegeneration , medicine , apolipoprotein e , pathogenesis , immunology , pathology , disease , inflammation
Background Increasing evidence implicates neuroinflammation in the pathogenesis of various neurological and psychiatric disorders. This is particularly true in neurodegenerative diseases. The NLRP3 inflammasome is a critical component of the innate immune response and its activation is implicated in neurodegenerative disease by emerging studies from both in vitro inflammatory assays and in vivo preclinical models. Method Post‐mortem samples were obtained from The Manchester Brain Bank and The Multiple Sclerosis and Parkinson’s Tissue Bank (London). Tissue collections comprised of age and sex matched non‐neurodegenerative controls and Alzheimer’s disease (AD) (temporal lobe; control: Braak stage 0‐II, mild AD: Braak stage III‐IV, severe AD: Braak stage V‐VI. N=40 per group) and Parkinson’s disease (PD) (frontal cortex and substantia nigra, control & PD, N=20 per group per region). Gene expression (mRNA) of NLRP3 and associated proinflammatory markers (AIF1, HLA‐DRA, PYCARD, CASP1, IL1B, IL18 and GFAP), were determined in brain tissues by RT‐qPCR. Aβ42 protein level was assessed in the AD cohort by ELISA. Results GFAP (a marker for activated astrocytes) was up‐regulated in severe AD patients compared with controls. This was not significantly related to carriage of the APOE ε4 allele and remained significant in both sex subgroups. Aβ42 protein was upregulated in severe AD group and higher in APOE ε4 carriers. GFAP correlated with Aβ42 but not with the expression of any of the NLRP3‐related proinflammatory markers, which themselves were not significantly changed in the neurodegenerative disease cohorts. Conclusion The results indicate that a relative increase in gene expression of the NLRP3 system as an inflammatory marker in neurodegenerative diseases may not be apparent, despite an increase in GFAP in severe AD. Although our data are contrary to previous findings from in vitro and in vivo preclinical studies, they are similar to other two post‐mortem human brain studies. It may be that data from animal models and in vitro studies, in which inflammatory processes are usually generated acutely with abundant stimuli, are not representative of the chronic neuroinflammation associated with neurodegenerative diseases. Future research with greater cell‐specificity and closer examination of protein function in this pathway in well‐characterised human cohorts is urgently needed.