PubMed: 24561250

The role of inflammasome in Alzheimer's disease.
Ageing research reviews
Chan C | Liu L

Evidence e8743b7d95

Activators include bacteria, virus, fungus, protoza, microbial proteins, crystalline urea, RNA, Alum, ATP, potassium efflux, fatty acids, Aβ, and most recently, degraded mitochondrial DNA (Liu et al., 2013a; Mathew et al., 2012; Schmidt and Lenz, 2012)

Evidence 885fcc1392

Phagocytosis and subsequent lysosomal damage trigger by Aβ initiate the activation of the NLRP3 inflammasome in the microglia (Halle et al., 2008)

Evidence f2ed427655

These studies highlighted the role of saturated fatty acids in the production of IL-1β by inflammasomes, i.e. NLRC4

Evidence 0fd949d948

Spinal cord injury elevates extracellular ATP levels during neuroinflammation, which may act on purinergic receptors to trigger the activation of inflammasome (de Rivero Vaccari et al., 2012; Minkiewicz et al., 2013)

Evidence be38892d50

ATP, a danger-associated molecular pattern that is released from damaged cells after brain injury, activates the NLRP2 inflammasome, which consists of the NLRP2 receptor, ASC and caspase-1, in human astrocytes (Minkiewicz et al., 2013)

Evidence 38ffd96116

The ATP-induced activation of the NLRP2 inflammasome interacts with the ATP-release pannexin 1 channel and ATP-gated P2X7 receptor leading to the maturation of IL-1β (Minkiewicz et al., 2013)

Evidence 62836a53a0

In human astrocytes, ATP released from damaged or dying cells after traumatic brain injury activates the NLRP2 inflammasome, leading to the maturation of both IL-1β and IL-18 (Minkiewicz et al., 2013)

Evidence ccc9727bf0

In addition, Brilliant Blue G (BBG), a P2X7 receptor antagonist, inhibits ATP-induced activation of the NLRP2 inflammasome in human astrocytes (Minkiewicz et al., 2013)

Evidence 35c9fe13d9

Palmitate, a fatty acid, activates the NLRC4 inflammasome in primary astrocytes leading to the release of IL-1β (Liu and Chan, 2014)

Evidence 05fa522854

Recently we identify that palmitate activates the NLRC4 inflammasome in primary astrocytes to release IL-1β, and ASC participates in the activation of the NLRC4 inflammasome (Liu and Chan, 2014)

Evidence f4111cb6d5

Probenecid, an inhibitor of pannexin 1, has been shown to significantly inhibit the expression and activation of the NLRP2 inflammasome, and the maturation of bothIL-1β and IL-18 in human astrocytes induced by ATP (Minkiewicz et al., 2013)

Evidence ae176bfc52

Probenecid has also been demonstrated to reduce the activation of the NLRP1 inflammasome, and improve the learning performance in age-related cognitive decline (Mawhinney et al., 2011)

Evidence d3b7411ada

In vivo and cell studies demonstrate that fibrillar Aβ activates the NLRP3 inflammasome which is composed of the NLRP3 receptor, ASC and caspase-1, to produce IL-1β in microglia (Halle et al., 2008)

Evidence aa110a6829

In response to danger signals, inflammasomes assemble by self-oligomerizing the NLRs through interactions with the NACHT domain (van de Veerdonk et al., 2011)

Evidence 61dd468e46

The activators of the inflammasomes can be divided into two categories; pathogen associated molecular patterns (PAMPs) activate a host-defense reaction, and damage associated molecular patterns (DAMPs) activate a self-defense mechanism in response to danger signals (Salminen et al., 2008)

Evidence 84f104c12c

Aging, another risk factor of AD, has been found to activate the NLRP1 inflammasome and upregulate IL-18 and IL-1β levels in the hippocampus of aged mice (Mawhinney et al., 2011)

Evidence 025137932f

In the CNS, the production of IL-1β by inflammasomes, specifically NLRP1, NLRP2, NLRP3 and NLRC4, is well-characterized as compared to other interleukins (Minkiewicz et al., 2013; Trendelenburg, 2008)

Evidence bbf5339a61

In addition, NLRC4 and ASC levels are upregulated in the brains of AD patients (Liu and Chan, 2014), suggesting a possible role of the NLRC4 inflammasome in AD pathogenesis

Evidence 821e892b05

Spinal cord injury can activate the NLRP1 inflammasome to produce IL-1β in rat spinal cord neurons (de Rivero Vaccari et al., 2008)

Evidence 837f1be19b

Spinal cord injury causes IL-18 and IL-1β release from neuronal cells through the activation of the NLRP1 inflammasome, composed of receptor NLRP1, adaptor protein ASC, caspase-1, caspase-11 and X-linked inhibitor of apoptosis protein (de Rivero Vaccari et al., 2008)

Evidence 4f795740ef

In support, a recent study in APP/PS1 mice confirms that the NLRP3 inflammasome contributes to the AD pathology (Heneka et al., 2013)

Evidence 7f773f4516

Similarly, inhibiting the NLRP3 inflammasome reduces the neuritic plaque burden in an AD transgenic mouse model (Shi et al., 2013)

Evidence 1c87f5ae9e

Inflammasomes involve in the maturation of IL-1β and IL-18 are expressed in neurons (de Rivero Vaccari et al., 2008; Yang-Wei Fann et al., 2013; Zou and Crews, 2012)

Evidence a3da9e7b27

IL-1β and IL-18 are synthesized as inactive precursors, proIL-1β and proIL-18, respectively, and require inflammasomes for their maturation

Evidence 74785089ac

However the maturation of IL-18 and IL-1β could be regulated by the same type of inflammasome

Evidence 77ea524c4f

Like IL-1β, in most cases, the mature secretable form of IL-18 is generated by caspase-1 through the activation of inflammasome

Evidence a376473487

As for the NLRP1 and NLRP3 inflammasomes, the oligomerzied NLRs recruit and interact with the adaptor protein ASC, which in turn recruits the effector protein procaspase-1 that is central to the activation of inflammasomes (Huang et al., 2013)

Evidence f50995612e

Caspase-1 is the protease that cleaves the precursor of the proinflammatory molecules to form their mature form, such as IL-1β and IL-18 (Schroder and Tschopp, 2010)

Evidence 9e900dca4e

For example, down-regulation of NLRP1 in macrophages trigger by Cordyceps sinensis mycelium reduces both IL-18 and IL-1β levels (Huang et al., 2013)

Evidence 0a7edad603

They include the adaptor protein, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which is an essential component of the NLRP1, NLRP2 and NLRP3 inflammasomes, but not of the more complex NLRC4 inflammasome (Martinon et al., 2009; Minkiewicz et al., 2013; Schroder and Tschopp, 2010)

Evidence a7b0f84bed

Under certain but not all conditions ASC (Martinon et al., 2009) or Naip5 (NLR family, apoptosis inhibitory protein 5) (Lightfield et al., 2011) is required for the activity of the NLRC4 inflammasome

Evidence 7a3cf1dc64

The adaptor protein ASC is important for the activation of NLRC4 inflammasome in astrocytes, while Naip 5 is not (Liu and Chan, 2014)

Evidence 3ddab850ec

ASC neutralization reduces the upregulation in IL-18 and IL-1β levels (de Rivero Vaccari et al., 2008)

Evidence 83b86d0ac8

Reducing NLRC4 or ASC levels in the palmitate (PA)-treated astrocytes significantly reduces IL-1β production (Liu and Chan, 2014)

Evidence dd34a34bd9

A subsequent study demonstrated that P2X7 purinergic receptor is involved in the activation of NLRP1 inflammasome (Silverman et al., 2009)

Evidence 650d98247d

Similarly, the P2X7 purinergic receptor has been shown to activate the NLRP1 inflammasome in primary neurons (Silverman et al., 2009)

Evidence 4ac624cee7

Deficiency of the NLRP3 gene reduces Aβ deposition and plays a protective role on memory and behavior (Heneka et al.,2013)

Evidence 99cc7c1c6c

Interleukins, in particular IL-1β and IL-18, are upregulated in AD brain, and the overexpression of IL-1β or IL-18 is critical for the onset of the inflammatory process (Rubio-Perez and Morillas-Ruiz, 2012), and both mediate the expression of a vast array of inflammatory genes (Weber et al., 2010)

Evidence e652580726

In support, knockout of NLRP3 and caspase-1 have been shown to suppress amyloidogenesis and neuropathology, and improve cognition in AD transgenic mice (Heneka et al., 2013)

Evidence 86d6a879a7

A recent report shows that IL-18 and IL-1β are secreted from primed murine dendritic cells in response to Listeria protein p60, but inhibiting NLRP3 reduces the production of IL-1β, but not IL-18 secretion (Schmidt and Lenz, 2012)

Evidence b558ca7e33

Given that P2X4 and P2X7 are the major purinergic P2X receptor subtypes, a study of spinal cord injury in P2X4 knock-out mice showed a significant reduction in inflammasome activation and proinflammatory cytokine production as compared to wild type (de Rivero Vaccari et al., 2012), supporting the involvement of purinergic receptor P2X4 in the activation of the NLRP1 inflammasome

Evidence 70a32235f7

However, upon further study of purinergic receptor P2X4 knockout mice with spinal cord injury, the production of IL-1β but not of IL-18 reduces in the neurons as compared with wild-type mice (de Rivero Vaccari et al., 2012)

Evidence 4bde981b0f

P2X4 knock-out mice has been shown to decrease the level of IL-1β and to have impair inflammasome signaling (de Rivero Vaccari et al., 2012)

Evidence 5e26ae2d5a

Trauma, a risk factor for AD, increases inflammasome expression in rat neurons (de Rivero Vaccari et al., 2009; de Rivero Vaccari et al., 2008)

Evidence f9fe7c12c8

Furthermore, postmortem brain tissues from stroke patients show increase protein levels of inflammasomes in primary cortical neurons (Yang- Wei Fann et al., 2013)


BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.