The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer's disease.

Marina Saresella,Federica Piancone,Mario Clerici,Elena Calabrese,Roberta Mancuso,Ivana Marventano,Veronica Rainone,Francesca La Rosa,Raffaello Nemni,Martina Zoppis

doi:10.1186/s13024-016-0088-1

Marina Saresella, Federica Piancone + Show 8 more

Open Access

https://doi.org/10.1186/s13024-016-0088-1

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Abstract

BackgroundInterleukin-1 beta (IL-1β) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer’s disease (AD); no conclusive data are nevertheless available in AD patients.ResultsmRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1β, IL-18) was up-regulated in severe and MILD AD. Monocytes co-expressing NLRP3 with caspase 1 or caspase 8 were significantly increased in severe AD alone, whereas those co-expressing NLRP1 and NLRP3 with PYCARD were augmented in both severe and MILD AD. Activation of the NLRP1 and NLRP3 inflammasomes in AD was confirmed by confocal microscopy proteins co-localization and by the significantly higher amounts of the pro-inflammatory cytokines IL-1β and IL-18 being produced by monocytes. In MCI, the expression of NLRP3, but not the one of PYCARD or caspase 1 was increased, indicating that functional inflammasomes are not assembled in these individuals: this was confirmed by lack of co-localization and of proinflammatory cytokines production.ConclusionsThe activation of at least two different inflammasome complexes explains AD-associated neuroinflammation. Strategies targeting inflammasome activation could be useful in the therapy of AD.

Highlights

Interleukin-1 beta (IL-1β) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer’s disease (AD); no conclusive data are available in AD patients
Up-regulation of inflammasome genes in LPS-primed and Aβ42-stimulated-monocytes of AD patients mRNA expression of 84 genes involved in the assembly, the activation, and the down-stream signalling of inflammosomes was quantified by qPCR in all patients and controls
Data obtained in LPS-primed and Aβ42−stimulated-monocytes, showed the presence of a significant upregulation involving genes, that codify for the proteins that form the inflammasome in MILD and severe AD, as well as in mild cognitive impairment (MCI)

Summary

Introduction

Interleukin-1 beta (IL-1β) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer’s disease (AD); no conclusive data are available in AD patients. Multiple signals, which are potentially provided in combination, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1β and IL-18 [8,9,10,11,12,13,14,15,16,17,18] These cytokines have a beneficial role in promoting inflammation and eliminating infectious pathogens, mutations that result in constitutive inflammasome activation and overproduction of IL-1β and IL-18 have been linked to inflammatory and autoimmune disorders [19,20,21]

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