The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease

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.

Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice

“…These data suggested a possible role for the inflammasome in AD and the observation that NLRP3-deficiency in the APP/PS1 mouse model decreased neuroinflammation and Aβ accumulation, and improved neuronal function, supports this hypothesis (Heneka et al, 2013). Notably, expression of several components of the inflammasome, including NLRP3 and caspase 1 as well as IL-1β and IL-18, is increased in monocytes from AD patients, and to a lesser extent from patients with mild cognitive impairment (Saresella et al, 2016). Recent evidence suggests that the rs10754558 variant of the NLRP3 gene confers a significant risk of late-onset AD, particularly in ApoE ε4 carriers and while the rs2027432 variant is also associated with increased risk, the rs35829419 variant (Q705K in NLRP3) is associated with protection (Tan et al, 2013).…”

“…An anti-IL-1R blocking antibody has been reported to reduce insoluble Aβ 1-42, fibrillar Aβ oligomers and large Aβ-containing plaques in brain tissue from 3xTg mice (Kitazawa et al, 2011) and IL-1β + microglia prepared from APP/PS1 mice had reduced Aβ compared with IL-1β − microglia (Saresella et al, 2016). The decrease in brain IL-1β in APP/PS1/NLRP3 −/− , was also accompanied by evidence of increased phagocytosis of Aβ by microglia, assessed by evaluating the presence of the amyloid dye methoxy-X04 using flow cytometry (Heneka et al, 2013).…”

Microglial NLRP3 Activity in Alzheimer's Disease

“…Monocytes from patients with severe AD have significantly greater NLRP3 activation compared to control groups [30]. Moreover, IL-1β levels are significantly increased in patients with early-onset AD [31].…”

“…Ojala, et al [27] Increase of IL-18 in AD brain Heneka, et al [37] Increase of Caspase-1 in AD brain Griffin, et al [29] IL-1β is involved in neuronal damage Saresella, et al [30] NLRP3 is upregulated in monocytes of severe AD patients Dursun, et al [31] IL-1β is significantly increased in serum of early-onset AD patients Chen, et al [32] IL-18 is increased in serum of AD patients…”

Deletion of the Inflammasome Sensor <b><i>Aim2</i></b> Mitigates Aβ Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model

“…Among these various sensors, NLRP3 is the most studied inflammasome sensor in AD [21][22][23][24][25][26] . NLRP3 inflammasomes serve as an Aβ sensor, triggering inflammation in the brain [22,23] .…”