International Immunopharmacology 49 (2017) 155–160

Contents lists available at ScienceDirect

International Immunopharmacology
journal homepage: www.elsevier.com/locate/intimp

Review

Amyloidogenic proteins associated with neurodegenerative diseases activate MARK

the NLRP3 inflammasome
Qian-hang Shaoa, Xiao-ling Zhanga, Peng-fei Yanga, Yu-he Yuana,⁎, Nai-hong Chena,b,⁎
a
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100050, China
b
College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China

A R T I C L E I N F O A B S T R A C T

Keywords: Neuroinflammation has been shown as an essential factor in the pathogenesis of neurodegenerative diseases,
α-Synuclein such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and Multiple Sclerosis.
Amyloid-β Furthermore, activated microglia and increased pro-inflammatory cytokines are the major hallmarks in neuro-
Inflammation degenerative diseases. A multimolecular complex named as inflammasome is involved in the process of in-
NLRP3 inflammasome
flammatory response, which can activate inflammatory caspases, leading to the cleavage and secretion of in-
Neurodegenerative disease
flammatory cytokines, and finally generates a potent inflammatory response. In neurodegenerative diseases, it
has been widely assumed that some types of amyloid proteins might be the triggers to activate the NLRP3
inflammasome. In this review, we summarize the current researches about the role of NLRP3 inflammasome, by
reviewing the main studies in vitro and in vivo experiments and discuss the potential for new therapeutic in-
terventions in neurodegenerative diseases.

1. Introduction disorders [6,7]. Interleukin-1β (IL-1β) has been demonstrated to be a

Neurodegenerative diseases in the central nervous system (CNS)
with inferior regenerative capacity are fundamentally characterized by
its distinct pathologic mechanisms, including axonal structure and
transport disruption, released harmful factors to extracellular matrix,
and neuroinflammation. Therefore, the therapies of neurodegenerative
diseases are faced with many challenges [1]. Neuroinflammation is an
important innate immune system response to injury and numerous
stimuli such as pathogens and metabolic toxic wastes [2]. Thus, neu-
roinflammation is now regarded as a crucial response not only to acute
injury in the CNS, but also to neurodegenerative diseases [3]. Although
unstable inflammation may not represent a central factor, many data in
animal models indicate that triggered inflammatory responses are in-
volved in the pathological progression of neurodegenerative disease
[4]. Microglia cells are the major phagocytes in the CNS and quickly
respond to pathogenic stimuli to protect the microenvironment of the
brain [5]. Additionally, abnormal activation of microglia and the in-
cremental secretion of many pro-inflammatory cytokines have been
generally observed during the development of neurodegenerative
primary mediator leading to neurodegenerative diseases, and its
abatement could account for the neuroprotective function in vitro and
in vivo experiments [8]. During the process of inflammatory response,
its production is regulated by a kind of multiprotein complexes termed
as inflammasome. The assembled inflammasome contributes to the
cleavage of procaspase-1 to mature caspase-1, and then mature caspase-
1 orderly activates the IL-1 pro-inflammatory cytokine [9,10]. In-
flammasome is considered as an intracellular sensor for infectious pa-
thogens as well as for host danger signals associated with neurode-
generative diseases [11]. It has been widely suggested that some similar
aggregated deposits, which are formed by amyloid fibrils of specific
proteins, such as amyloid-β protein in Alzheimer's disease (AD), α-sy-
nuclein protein in Parkinson's Disease (PD) and amyloid protein in
Huntington's disease (HD), play important roles in the pathogenesis of
related diseases [12,13]. These proteins share in a common trend to
form amyloid-like structures and alter towards folding pathways, along
with their intrinsic structure, which called cross-β structure. This spe-
cific structure may represent a new generic amyloid fibrils recognized
by the innate immune system [14]. In addition, accumulating evidences

Abbreviations: AD, Alzheimer's disease; ANSC, adult neural stem cell; Aβ, amyloid-β protein; CNS, central nervous system; DAMPs, danger-associated molecular patterns; IL-1, in-
terleukin-1; LBs, Lewy bodies; NFTs, neurofibrillary tangles; NLRs, NOD-like receptors; PAMPs, pathogen-associated molecular patterns; PD, Parkinson's disease; PRRs, pattern re-
cognition receptors; ROS, reactive oxygen species; SNpc, substantia nigra pars compacta; TLRs, toll-like receptors
⁎
Corresponding authors at: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, I, Xiannongtan Street,
Xicheng District, Beijing 100050, China.
E-mail addresses: yuanyuhe@imm.ac.cn (Y.-h. Yuan), chennh@imm.ac.cn (N.-h. Chen).

http://dx.doi.org/10.1016/j.intimp.2017.05.027
Received 7 March 2017; Received in revised form 12 May 2017; Accepted 22 May 2017
1567-5769/ © 2017 Elsevier B.V. All rights reserved.
Q.-h. Shao et al.
suggest that unique amyloid proteins can be sensed by the NLRP3 in-
flammasome and provide an underlying mechanism for IL-1 production
in neurodegenerative diseases [15,16]. In this review, we discuss the
recent findings about NLRP3 inflammasome, speculate its potential role
in neurodegenerative diseases, and present the challenges in targeting
NLRP3 inflammasome for therapeutic purposes.
2. The NLRP3 inflammasome and inflammatory cytokine IL-1 in
neurodegenerative diseases
The response of the innate immune system plays a significant role
against acute injury in the CNS by pattern recognition receptors (PRRs)
such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). PRRs
mainly express at microglia, astrocyte and macrophage, which can act
as intracellular sensors to recognize a variety of danger-associated
molecular patterns (DAMPs) and pathogen-associated molecular pat-
terns (PAMPs) [17,18]. There are more than twenty NLR genes in hu-
mans and over thirty NLR genes in mice [19,20]. NLRs are divided into
different groups and each of them has unique response to DAMPs [21].
Every NLR family member differs from each other since they have
various N-terminal protein domain structures [22]. Among all kinds of
NLRs, the inflammasome-forming NLR is the most particularly studied
complex. The concept of inflammasome was firstly described by Mar-
tinon et al. in the early 2000s, when many scientists reported the spe-
cific identification of a caspase-triggering complex [23]. The in-
flammasome is an intracellular multiprotein complex, which is defined
by its exclusive NLR protein, including NLRP1 [24], NLRP3 [25],
NLRC4 [26], NLRP6 [27], NLRP7 [28], as well as the HIN-200 family
member named as AIM2, without NLR inflammasome receptor and
directly binding cytosolic DNA [29]. However, only several kinds of
inflammasomes have been recognized in the CNS: the NLRP1 in-
flammasome in neuron, the NLRP2 inflammasome in astrocyte, and the
NLRP3 inflammasome in microglia. All inflammasomes generally have
three main components, containing a nucleating PRR, apoptosis-asso-
ciated speck-like adapter protein containing a CARD (ASC) and the
downstream effector enzyme caspase-1 [30] (Fig. 1).
NLRP3 inflammasome is the most thoroughly discussed inflamma-
some in the CNS so far, due to that a large number of signals can make it
active [31], such as PAMPs, protozoan pathogens and toxins from
bacteria [32], viral components [33], fungal [34], in addition, DAMPs
such as extracellular ATP [35], various crystals [36], and amyloid-β
Fig. 1. The structure and function of NLRP3 inflammasome. The danger signals can cause
assembly and activation of NLRP3 inflammasome. NLRP3 inflammasome results in cas-
pase-1 activation and subsequently activated caspase-1 leads to the maturation of IL-1β.
LRR, leucine-rich repeat; NACHT, nucleotide binding and oligomerization domain; PYD,
pyrin-only domain; ASC, apoptosis-related speck-like protein containing a caspase re-
cruitment domain; CARD, caspase activation and recruitment domain.
156
International Immunopharmacology 49 (2017) 155–160
fibrils [37]. Moreover, recent studies have illustrated cation flux, mi-
tochondrial dysfunction and ER stress are also involved in the activa-
tion of the NLRP3 inflammasome [38]. The truth that many stimuli
cause NLRP3 activation indicates that the NLRP3 inflammasome acts as
a major sensor of cellular damage signals. Depending on abundant ex-
periments, the NLRP3 inflammasome activation has been considered
through three major ways: abnormal expression level of specific cations
[39,40], serious oxidative stress with reactive oxygen species (ROS)
production [41], and phagosomal dysfunction with the lysosome rup-
ture [42]. Tissue expression researches show that the expression of
NLRP3 inflammasome main components is found in the CNS [43].
Recently, one study has definitively demonstrated that microglia can
express the main components of NLRP3 inflammasome but astrocyte
cannot [44]. Interestingly, microglial cells are the major response cells
of immune system in the CNS. And specific relevant proteins of neu-
rological diseases that are thought to be the triggers for NLRP3 in-
flammasome activation in CNS cells, including amyloid-β [45] and α-
synuclein [46]. Therefore, the NLRP3 signaling plays a critical role in
the inflammatory response of the CNS.
IL-1 is a master cytokine that mediates both the innate and adaptive
immune responses, leading to the production of other cytokines such as
IL-6 or tumor necrosis factor α (TNF-α) [6,47]. IL-1 is a 17 kDa protein
classified into two distinct isoforms, IL-1α and IL-1β [48], and is the
initial identified cytokine related with active actions in the brain.
Meanwhile, many studies have supported that pro-inflammatory IL-1β
plays a master role in the neurodegenerative diseases [11,49]. Re-
markably, activation of microglia by lipopolysaccharide (LPS) causes
symptoms of PD in wild-type mice. However, it was observed that LPS-
induced functional changes of learning and memory did not occur in IL-
1-knockout (KO) mice [50]. In one research, IL-1 receptor antagonist
knockout mice showed up-regulation of microglial neuroinflammation
and enhanced neuronal damage caused by infusing human amyloid-β
when compared with wild-type mice [51]. Two signal pathways are
necessary in the production of biologically active IL-1β, the first signal
is needed to upregulate the level of mRNA, which can be achieved by
the activation of NF-κB pathway via TLRs. Following this, the second
signal pathway is to assemble the inflammasome complex and cleavage
of pro-IL-1β by caspase-1 activation [15,22,52]. Furthermore, the in-
flammasome is proved to be a key regulator in the secretion process of
IL-1β [53,54]. A variety of stimuli associated with infection or cellular
stress can cause the inflammasome assembly, and subsequently re-
sulting in the cleavage of caspase-1 from its pro-form to its en-
zymatically active form. The active caspase-1 constitutively mediated
the cleavage of several cytokines, such as pro-IL-1β and pro-IL-18 into
the mature forms IL-1β and IL-18 [55]. Additionally, all these cytokines
contribute to the pathological process of neurodegenerative diseases
[56,57].
3. The NLRP3 inflammasome and amyloid-β in AD
Alzheimer's disease (AD) is the most common neurodegenerative
disease, it is estimated that more than 27 million people are affected all
over the world [58]. In the AD patients' brains, there are two important
neuropathology markers, one is neurofibrillary tangles (NFTs) and the
other is senile (amyloid) plaques [59]. The senile plaques are located at
extracellular sections and surrounded by activated microglia and as-
trocyte, which are formed by the insoluble amyloid-β protein fibrils
(Aβ). What is more, Aβ is a pathological protein that has been found to
be most clearly associated with the pathogenesis [60]. Inflammation
significantly contributes to the pathogenic process of AD, with in-
creased expression of inflammatory cytokines and neurotoxins [61],
one important cytokine involved in AD is IL-1β [62]. Extensive evi-
dences have demonstrated that Aβ fibrils have the unique structural
features, which can be the pro-inflammatory signal identified by TLRs,
along with activating NF-κB pathway [45], phosphorylated cAMP re-
sponse element binding protein (CREB) [63] and finally inducing the
Q.-h. Shao et al.
activation of microglia [64,65]. Although the exact pathogenesis of AD
is not fully understood, it is considered that Aβ accumulation induces
persistent inflammation leading to neuronal dysfunction, which is
suggested to be a potential mechanism of the progressive neurode-
generation in AD [66].
Recently, the activation of the NLRP3 inflammasome attracts much
attention, which may be an alternative signaling pathway of Aβ binding
downstream [67,68]. Further supports for this idea come from studies
of a vivo experiment, double transgenic mice associated with familial
AD mutations which have human APP protein over expression, when
the NLRP3 inflammasome have an apparent deficiency, it performs an
improvement in AD pathology and is protected from the tissue damage
[68,69]. In vitro, primary microglia stimulated by fibrillar Aβ increases
the release of IL-1βand the process depends on the activation of cas-
pase-1 and NLRP3 inflammasome [70]. Importantly, in this experiment,
it has also indicated that Aβ toxicity owing to IL-1β can be removed by
the genetic deletion of caspase-1 [37]. In the vivo and vitro experiments,
these data showed that Aβ fibrils could provide both priming and ac-
tivation signals. Activation of the TLR pathway represented “signal 1”
and Aβ fibrils stimulated a dramatic upregulation of IL-1β and TNF-α
mRNA and an increase in pro-IL-1β. Aβ fibrils also clearly provided
“signal 2” which involved activation of the NLRP3inflammasome and
conversion of pro-IL-1β to mature IL-1β [71,72]. Hence, it is clear that
Aβ fibrils are able to stimulate both priming and activation of the
NLRP3 inflammasome, and the activated NLRP3 inflammasome in mi-
croglia is fundamental for IL-1β maturation and secretion [68,73]. As
shown in recent researches, some findings prove that the NLRP3 in-
flammasome was activated when it sensed the lysosomal rupture,
whereby the phagocytosed Aβ triggered an abnormal lysosomal re-
sponse and release of lysosomal protease cathepsin B [74]. Cathepsin B
is associated with the pathogenesis of AD, plenty of cathepsin B is found
in activated microglia surrounding the senile plaques [75]. Inhibition of
the cathepsin B can apparently suppress NLRP3 inflammasome activa-
tion, decrease Aβ deposition in the brain and improve spatial memory
[76]. In one recent context, using Aβ treated rat primary microglial
cells, experimental data suggest cathepsin B plays an essential role in
the process of NLRP3 inflammasome activation [77]. However, the in-
depth mechanisms of cathepsin B and whether this phenomenon can
exist in AD animal models remain unclear. Additionally, autophagy is
similarly essential for the regulation of Aβ-induced NLRP3 inflamma-
some activation. Study demonstrates that autophagic process in mi-
croglia is impaired during Aβ treatment, resulting in counteracting Aβ
clearance and serious deposition, it may aggravate inflammatory re-
sponse and activation of NLRP3 inflammasome [78] (Fig. 2). In con-
clusion, studies above have offered a fine prospect to the therapeutic
target of NLRP3 inflammasome in AD progression and further re-
searches are needed to elucidate the detailed mechanisms of in-
flammasome contributing to AD pathology.
4. The NLRP3 inflammasome and α-synuclein in PD
Parkinson's disease (PD) is the second most common age-related
neurodegenerative disease in the world after Alzheimer's disease, and
has influenced nearly 1.5% of the population over the age of 65 years
old [79,80]. PD is a multi-factorial disease, characterized by the pro-
gressive degeneration of dopamine (DA) neurons in the substantia nigra
pars compacta (SNpc) [80] and the presence of Lewy bodies (LBs) in the
brain, mainly composed of aggregated and misfolded α-synuclein pro-
tein, a neurodegenerative disease-related amyloidogenic peptides pro-
tein. Significant inflammatory markers such as activated microglia and
cytokines can be found in the SN of PD patients' brains and also have
been found in several simulative animal models [81–83]. Thus neu-
roinflammation and immune system response can be considered not
only as determinant risk factor in the disease progression but also as a
pathogenic factor in the occurring of PD [84]. The specific molecular
mechanisms underlying neuroinflammation are still unknown,
157
International Immunopharmacology 49 (2017) 155–160
although it is already clear that α-synuclein protein is related in this
process.
Numerous studies have reported that aggregated α-synuclein is
toxic to microglia, furthermore, α-synuclein abnormal regulation exerts
a critical role in PD pathology [85,86]. In addition to amyloid-β, we
focused on the possibility of aggregated α-synuclein on NLRP3 in-
flammasome activation, and its pro-inflammatory abilities as an amy-
loidogenic peptide [46,87]. Current experimental results have demon-
strated that aggregated α-synuclein acts as an endogenous disease-
related signal, and induces microglia to release pro-inflammatory cy-
tokines such as TNF-α and IL-1β [87,88]. It is potent that aggregated
and misfolded protein is sensed by the NLRP3 inflammasome, providing
a unique mechanism for IL-1β production [15]. Specially, two hall-
marks of inflammasome activation, mature IL-1β release and caspase-1
activation are found to be enhanced in the substantia nigra of PD pa-
tients [89]. In addition, some work data provide the evidences that the
pro-inflammatory activity is exerted by fibrillar and monomeric α-sy-
nuclein, finding that both of them can induce monocytes to promote the
expression of pro-IL-1β, engaging with cell-membrane receptor TLR.
But only α-synuclein fibrils can induce the release of the mature form of
IL-1β, thereby activating NF-κB pathway and the NLRP3 inflamma-
some, respectively [46,90,91]. In many researches, it supports the
opinion that α-synuclein oligomer is the primary neurotoxic form in the
process of disease [92], whereas surprisingly, oligomer is unable to
trigger NLRP3 inflammasome assembly and induce IL-1β secretion
[90]. α-Synuclein fibrils have their intrinsic cross-β structure, which
could be identified by innate immunity and activate the inflammasome.
In one research, experimental results show that α-synuclein fibrils can
induce damage of proliferation in neurospheres in adult neural stem
cells (ANSCs) and activate both TLR/NF-κB pathway and NLRP3/cas-
pase-1 signals in ANSCs. Both NLRP3 inflammasome knockdown and
caspase-1 knockout could recover impaired neurogenesis in ANSCs.
These findings completely prove that NLRP3-inflammasome-mediated
inflammatory pathway plays an essential role in the process of neuro-
genesis impairment induced by α-synuclein [91,93].
Meanwhile, experimental studies have demonstrated that ag-
gregated α-synuclein can be internalized by the cellular endocytic
pathways [94] and the internalized α-synuclein generates a rupture of
intracellular lysosomes. This rupture induces a cathepsin B dependent
increase of ROS production in THP-1 cell [95], finally results in NLRP3
inflammasome activation in these cells [96]. The observation that α-
synuclein fibrils induced-inflammasome activation in similar cell line of
microglia convinces us that the NLRP3 inflammasome is relevant to the
neuroinflammatory in PD. Moreover, experiment investigates the role
of phagocytosis and lysosomal function in α-synuclein peptides-induced
NLRP3 inflammasome activation, and interestingly finds that the in-
hibition of phagocytosis and lysosomal acidification significantly re-
strain inflammasome activation [97]. So all these results make a better
understanding of the mechanisms of the NLRP3 inflammasome activa-
tion, and find the direct interaction between microglia activation and
neurotoxic amyloidogenic peptides. In future, it is worthy to explore the
possibility of using an inflammasome antagonist as a new therapeutic
candidate in PD.
5. Conclusion
This review evaluates the role of inflammasome, especially em-
phasizing the role of NLRP3 inflammasome in neurodegenerative dis-
eases. Neurodegenerative diseases are characterized by the aggregation
of amyloidogenic protein, which are not considered to be typical in-
flammatory diseases, but sufficient evidences show that inflammatory
responses contribute to the pathogenesis. If we can control the neu-
roinflammation, it may alleviate the process of neurodegeneration.
NLRP3 inflammasome plays a vital role in the pathological process of
neurodegenerative disorders, such as AD and PD, and acts as a common
sensor for the identification of amyloidogenic proteins. Although
Q.-h. Shao et al.
considerable efforts have been done, our current knowledge about how
NLRP3 inflammasome can be activated is not precise. In existing re-
sults, it has proved that aggregated amyloid-β and α-synuclein fibrils
could promote the activation of NLRP3 inflammasome via activating
TLR/NF-κB pathway, inducing lysosomal rupture and cathepsin B re-
lease. There are a series of promising therapeutic measures that target
the NLRP3 inflammasome signaling including anti-IL-1 therapy, small
molecule NLRP3 inhibitors and other compounds. However, a key step
forward is to find out the specific brain regions of inflammasome ac-
tivation and specific cell types during these diseases. Further in-
vestigation and illumination of the underlying molecular mechanisms
about NLRP3 inflammasome activation have a great value. Hence, this
review highlights that NLRP3 inflammasome therapeutic intervention
can be a potential target for the prevention or treatment of neurode-
generative diseases.
Conflict of interest
The authors have declared no conflict of interest.
Acknowledgments
This work was supported by Beijing Natural Science Foundation
(NO. 7161011), National Natural Science Foundation of China Grants
(U1402221, 81573640, 81373997) and the Beijing Key Laboratory of
New Drug Mechanisms and Pharmacological Evaluation Study
(BZ0150).
References
[1] J. Nagai, R. Baba, T. Ohshima, CRMPs function in neurons and glial cells: potential
therapeutic targets for neurodegenerative diseases and CNS injury, Mol. Neurobiol.
(2016).
[2] J.G. Walsh, D.A. Muruve, C. Power, Inflammasomes in the CNS, Nat. Rev. Neurosci.
15 (2) (2014) 84–97.
[3] S.S. Shaftel, W.S. Griffin, M.K. O'Banion, The role of interleukin-1 in neuroin-
flammation and Alzheimer disease: an evolving perspective, J. Neuroinflammation
5 (2008) 7.
158
International Immunopharmacology 49 (2017) 155–160
Fig. 2. Priming and subsequent activation of NLRP3 in-
flammasome by amyloidogenic proteins. The priming
(signal 1) of NLRP3 inflammasome is provided by activating
TLR/NF-κB pathway, leading to the transcription of pro-IL-
1β and pro-IL-18. The phagocytosis of amyloidogenic pro-
teins can induce lysosomal rupture and augment the release
of cathepsin B (signal 2), which contributes to NLRP3, ASC
and caspase-1 protein complex formation. Consequently,
this complex activates caspase-1, generating mature cyto-
kines IL-1β and IL-18.
[4] C.K. Glass, K. Saijo, B. Winner, M.C. Marchetto, F.H. Gage, Mechanisms underlying
inflammation in neurodegeneration, Cell 140 (6) (2010) 918–934.
[5] L. Du, Y. Zhang, Y. Chen, J. Zhu, Y. Yang, H.L. Zhang, Role of microglia in neu-
rological disorders and their potentials as a therapeutic target, Mol. Neurobiol.
(2016).
[6] G. Trendelenburg, Acute neurodegeneration and the inflammasome: central pro-
cessor for danger signals and the inflammatory response? J. Cereb. Blood Flow
Metab. 28 (5) (2008) 867–881.
[7] M. Prinz, J. Priller, S.S. Sisodia, R.M. Ransohoff, Heterogeneity of CNS myeloid cells
and their roles in neurodegeneration, Nat. Neurosci. 14 (10) (2011) 1227–1235.
[8] R. Patejdl, I.K. Penner, T.K. Noack, U.K. Zettl, Multiple sclerosis and fatigue: a re-
view on the contribution of inflammation and immune-mediated neurodegenera-
tion, Autoimmun. Rev. 15 (3) (2016) 210–220.
[9] K.H. Mills, L.S. Dungan, S.A. Jones, J. Harris, The role of inflammasome-derived IL-
1 in driving IL-17 responses, J. Leukoc. Biol. 93 (4) (2013) 489–497.
[10] M. Lamkanfi, L. Vande Walle, T.D. Kanneganti, Deregulated inflammasome sig-
naling in disease, Immunol. Rev. 243 (1) (2011) 163–173.
[11] G. Singhal, E.J. Jaehne, F. Corrigan, C. Toben, B.T. Baune, Inflammasomes in
neuroinflammation and changes in brain function: a focused review, Front.
Neurosci. 8 (2014) 315.
[12] F. Chiti, C.M. Dobson, Protein misfolding, functional amyloid, and human disease,
Annu. Rev. Biochem. 75 (2006) 333–366.
[13] R. Hanamsagar, M.L. Hanke, T. Kielian, Toll-like receptor (TLR) and inflammasome
actions in the central nervous system, Trends Immunol. 33 (7) (2012) 333–342.
[14] M. Margittai, R. Langen, Fibrils with parallel in-register structure constitute a major
class of amyloid fibrils: molecular insights from electron paramagnetic resonance
spectroscopy, Q. Rev. Biophys. 41 (3–4) (2008) 265–297.
[15] S.L. Masters, L.A. O'Neill, Disease-associated amyloid and misfolded protein ag-
gregates activate the inflammasome, Trends Mol. Med. 17 (5) (2011) 276–282.
[16] M. Lamkanfi, V.M. Dixit, Mechanisms and functions of inflammasomes, Cell 157 (5)
(2014) 1013–1022.
[17] P.H. Saavedra, D. Demon, H. Van Gorp, M. Lamkanfi, Protective and detrimental
roles of inflammasomes in disease, Semin. Immunopathol. 37 (4) (2015) 313–322.
[18] C.M. Volpe, P.M. Anjos, J.A. Nogueira-Machado, Inflammasome as a new ther-
apeutic target for diabetic complications, Recent Pat. Endocr. Metab. Immune Drug
Discov. (2016).
[19] J.C. Reed, K. Doctor, A. Rojas, J.M. Zapata, C. Stehlik, L. Fiorentino, J. Damiano,
W. Roth, S. Matsuzawa, R. Newman, S. Takayama, H. Marusawa, F. Xu, G. Salvesen,
A. Godzik, Comparative analysis of apoptosis and inflammation genes of mice and
humans, Genome Res. 13 (6b) (2003) 1376–1388.
[20] J.P. Ting, R.C. Lovering, E.S. Alnemri, J. Bertin, J.M. Boss, B.K. Davis, R.A. Flavell,
S.E. Girardin, A. Godzik, J.A. Harton, H.M. Hoffman, J.P. Hugot, N. Inohara,
A. Mackenzie, L.J. Maltais, G. Nunez, Y. Ogura, L.A. Otten, D. Philpott, J.C. Reed,
W. Reith, S. Schreiber, V. Steimle, P.A. Ward, The NLR gene family: a standard
nomenclature, Immunity 28 (3) (2008) 285–287.
[21] L.C. Freeman, J.P. Ting, The pathogenic role of the inflammasome in neurode-
generative diseases, J. Neurochem. 136 (Suppl. 1) (2016) 29–38.
[22] M.R. de Zoete, R.A. Flavell, Interactions between Nod-like receptors and intestinal
Q.-h. Shao et al.
bacteria, Front. Immunol. 4 (2013) 462.
[23] F. Martinon, K. Burns, J. Tschopp, The inflammasome: a molecular platform trig-
gering activation of inflammatory caspases and processing of proIL-beta, Mol. Cell
10 (2) (2002) 417–426.
[24] E.D. Boyden, W.F. Dietrich, Nalp1b controls mouse macrophage susceptibility to
anthrax lethal toxin, Nat. Genet. 38 (2) (2006) 240–244.
[25] S.B. Liu, W.L. Mi, Y.Q. Wang, Research progress on the NLRP3 inflammasome and
its role in the central nervous system, Neurosci. Bull. 29 (6) (2013) 779–787.
[26] F.S. Sutterwala, R.A. Flavell, NLRC4/IPAF: a CARD carrying member of the NLR
family, Clin. Immunol. 130 (1) (2009) 2–6.
[27] M. Wlodarska, C.A. Thaiss, R. Nowarski, J. Henao-Mejia, J.P. Zhang, E.M. Brown,
G. Frankel, M. Levy, M.N. Katz, W.M. Philbrick, E. Elinav, B.B. Finlay, R.A. Flavell,
NLRP6 inflammasome orchestrates the colonic host-microbial interface by reg-
ulating goblet cell mucus secretion, Cell 156 (5) (2014) 1045–1059.
[28] S. Khare, A. Dorfleutner, N.B. Bryan, C. Yun, A.D. Radian, L. de Almeida,
Y. Rojanasakul, C. Stehlik, An NLRP7-containing inflammasome mediates re-
cognition of microbial lipopeptides in human macrophages, Immunity 36 (3)
(2012) 464–476.
[29] S.M. Man, R. Karki, T.D. Kanneganti, AIM2 inflammasome in infection, cancer, and
autoimmunity: role in DNA sensing, inflammation, and innate immunity, Eur. J.
Immunol. 46 (2) (2016) 269–280.
[30] M. Keller, A. Ruegg, S. Werner, H.D. Beer, Active caspase-1 is a regulator of un-
conventional protein secretion, Cell 132 (5) (2008) 818–831.
[31] E.K. Jo, J.K. Kim, D.M. Shin, C. Sasakawa, Molecular mechanisms regulating NLRP3
inflammasome activation, Cell Mol. Immunol. 13 (2) (2016) 148–159.
[32] S. Mariathasan, D.S. Weiss, K. Newton, J. McBride, K. O'Rourke, M. Roose-Girma,
W.P. Lee, Y. Weinrauch, D.M. Monack, V.M. Dixit, Cryopyrin activates the in-
flammasome in response to toxins and ATP, Nature 440 (7081) (2006) 228–232.
[33] I.C. Allen, M.A. Scull, C.B. Moore, E.K. Holl, E. McElvania-TeKippe, D.J. Taxman,
E.H. Guthrie, R.J. Pickles, J.P. Ting, The NLRP3 inflammasome mediates in vivo
innate immunity to influenza A virus through recognition of viral RNA, Immunity
30 (4) (2009) 556–565.
[34] S. Joly, N. Ma, J.J. Sadler, D.R. Soll, S.L. Cassel, F.S. Sutterwala, Cutting edge:
Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome,
J. Immunol. 183 (6) (2009) 3578–3581.
[35] M. Karmakar, M.A. Katsnelson, G.R. Dubyak, Neutrophil P2X7 Receptors Mediate
NLRP3 Inflammasome-dependent IL-1beta Secretion in Response to ATP, 7 (2016),
p. 10555.
[36] P. Duewell, H. Kono, K.J. Rayner, C.M. Sirois, G. Vladimer, F.G. Bauernfeind,
G.S. Abela, L. Franchi, G. Nunez, M. Schnurr, T. Espevik, E. Lien, K.A. Fitzgerald,
K.L. Rock, K.J. Moore, S.D. Wright, V. Hornung, E. Latz, NLRP3 inflammasomes are
required for atherogenesis and activated by cholesterol crystals, Nature 464 (7293)
(2010) 1357–1361.
[37] A. Halle, V. Hornung, G.C. Petzold, C.R. Stewart, B.G. Monks, T. Reinheckel,
K.A. Fitzgerald, E. Latz, K.J. Moore, D.T. Golenbock, The NALP3 inflammasome is
involved in the innate immune response to amyloid-beta, Nat. Immunol. 9 (8)
(2008) 857–865.
[38] E.I. Elliott, F.S. Sutterwala, Initiation and perpetuation of NLRP3 inflammasome
activation and assembly, Immunol. Rev. 265 (1) (2015) 35–52.
[39] T. Murakami, J. Ockinger, J. Yu, V. Byles, A. McColl, A.M. Hofer, T. Horng, Critical
role for calcium mobilization in activation of the NLRP3 inflammasome, Proc. Natl.
Acad. Sci. U. S. A. 109 (28) (2012) 11282–11287.
[40] M. Lamkanfi, V.M. Dixit, Inflammasomes: guardians of cytosolic sanctity, Immunol.
Rev. 227 (1) (2009) 95–105.
[41] J. Tschopp, K. Schroder, NLRP3 inflammasome activation: the convergence of
multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10 (3) (2010)
210–215.
[42] C. Jin, P. Frayssinet, R. Pelker, D. Cwirka, B. Hu, A. Vignery, S.C. Eisenbarth,
R.A. Flavell, NLRP3 inflammasome plays a critical role in the pathogenesis of hy-
droxyapatite-associated arthropathy, Proc. Natl. Acad. Sci. U. S. A. 108 (36) (2011)
14867–14872.
[43] Y. Yin, Y. Yan, X. Jiang, J. Mai, N.C. Chen, H. Wang, X.F. Yang, Inflammasomes are
differentially expressed in cardiovascular and other tissues, Int. J. Immunopathol.
Pharmacol. 22 (2) (2009) 311–322.
[44] A. Gustin, M. Kirchmeyer, E. Koncina, P. Felten, S. Losciuto, T. Heurtaux,
A. Tardivel, P. Heuschling, C. Dostert, NLRP3 inflammasome is expressed and
functional in mouse brain microglia but not in astrocytes, PLoS One 10 (6) (2015)
e0130624.
[45] S.E. Terrill-Usery, M.J. Mohan, M.R. Nichols, Amyloid-beta(1-42) protofibrils sti-
mulate a quantum of secreted IL-1beta despite significant intracellular IL-1beta
accumulation in microglia, Biochim. Biophys. Acta 1842 (11) (2014) 2276–2285.
[46] G. Codolo, N. Plotegher, T. Pozzobon, M. Brucale, I. Tessari, L. Bubacco, M. de
Bernard, Triggering of inflammasome by aggregated alpha-synuclein, an in-
flammatory response in synucleinopathies, PLoS One 8 (1) (2013) e55375.
[47] L. Steinman, Inflammatory cytokines at the summits of pathological signal cascades
in brain diseases, Sci. Signal 6 (258) (2013) pe3.
[48] S.M. Allan, P.J. Tyrrell, N.J. Rothwell, Interleukin-1 and neuronal injury, Nat. Rev.
Immunol. 5 (8) (2005) 629–640.
[49] J.A. Smith, A. Das, S.K. Ray, N.L. Banik, Role of pro-inflammatory cytokines re-
leased from microglia in neurodegenerative diseases, Brain Res. Bull. 87 (1) (2012)
10–20.
[50] S. Tanaka, A. Ishii, H. Ohtaki, S. Shioda, T. Yoshida, S. Numazawa, Activation of
microglia induces symptoms of Parkinson's disease in wild-type, but not in IL-1
knockout mice, J. Neuroinflammation 10 (2013) 143.
[51] J.M. Craft, D.M. Watterson, E. Hirsch, L.J. Van Eldik, Interleukin 1 receptor an-
tagonist knockout mice show enhanced microglial activation and neuronal damage
159
International Immunopharmacology 49 (2017) 155–160
induced by intracerebroventricular infusion of human beta-amyloid, J.
Neuroinflammation 2 (2005) 15.
[52] L.A. Joosten, S. Abdollahi-Roodsaz, C.A. Dinarello, L. O'Neill, M.G. Netea, Toll-like
receptors and chronic inflammation in rheumatic diseases: new developments, Nat.
Rev. Rheumatol. 12 (6) (2016) 344–357.
[53] M.G. Netea, F.L. van de Veerdonk, J.W. van der Meer, C.A. Dinarello, L.A. Joosten,
Inflammasome-independent regulation of IL-1-family cytokines, Annu. Rev.
Immunol. 33 (2015) 49–77.
[54] S.M. Man, T.D. Kanneganti, Regulation of inflammasome activation, Immunol. Rev.
265 (1) (2015) 6–21.
[55] M.R. de Zoete, N.W. Palm, S. Zhu, R.A. Flavell, Inflammasomes, Cold Spring Harb.
Perspect. Biol. 6 (12) (2014) a016287.
[56] H. Hong, B.S. Kim, H.I. Im, Pathophysiological role of neuroinflammation in neu-
rodegenerative diseases and psychiatric disorders, Int. Neurourol. J. 20 (Suppl. 1)
(2016) S2–S7.
[57] M.L. Block, J.S. Hong, Microglia and inflammation-mediated neurodegeneration:
multiple triggers with a common mechanism, Prog. Neurobiol. 76 (2) (2005) 77–98.
[58] A. Wimo, L. Jonsson, B. Winblad, An estimate of the worldwide prevalence and
direct costs of dementia in 2003, Dement. Geriatr. Cogn. Disord. 21 (3) (2006)
175–181.
[59] C.L. Masters, D.J. Selkoe, Biochemistry of amyloid beta-protein and amyloid de-
posits in Alzheimer disease, Cold Spring Harb. Perspect. Med. 2 (6) (2012)
a006262.
[60] M.I. Aguilar, D.H. Small, Surface plasmon resonance for the analysis of beta-amy-
loid interactions and fibril formation in Alzheimer's disease research, Neurotox. Res.
7 (1–2) (2005) 17–27.
[61] K. Morimoto, J. Horio, H. Satoh, L. Sue, T. Beach, S. Arita, I. Tooyama, Y. Konishi,
Expression profiles of cytokines in the brains of Alzheimer's disease (AD) patients
compared to the brains of non-demented patients with and without increasing AD
pathology, J. Alzheimers Dis. 25 (1) (2011) 59–76.
[62] J.M. Rubio-Perez, J.M. Morillas-Ruiz, A review: inflammatory process in
Alzheimer's disease, role of cytokines, ScientificWorldJournal 2012 (2012) 756357.
[63] C. Cunningham, Microglia and neurodegeneration: the role of systemic inflamma-
tion, Glia 61 (1) (2013) 71–90.
[64] J.E. Lim, J. Kou, M. Song, A. Pattanayak, J. Jin, R. Lalonde, K. Fukuchi, MyD88
deficiency ameliorates beta-amyloidosis in an animal model of Alzheimer's disease,
Am. J. Pathol. 179 (3) (2011) 1095–1103.
[65] G.J. Rapsinski, M.A. Wynosky-Dolfi, G.O. Oppong, S.A. Tursi, R.P. Wilson,
I.E. Brodsky, C. Tukel, Toll-like receptor 2 and NLRP3 cooperate to recognize a
functional bacterial amyloid, curli, Infect. Immun. 83 (2) (2015) 693–701.
[66] T. Wyss-Coray, J. Rogers, Inflammation in Alzheimer disease—a brief review of the
basic science and clinical literature, Cold Spring Harb. Perspect. Med. 2 (1) (2012)
a006346.
[67] F.J. Sheedy, A. Grebe, K.J. Rayner, P. Kalantari, B. Ramkhelawon, S.B. Carpenter,
C.E. Becker, H.N. Ediriweera, A.E. Mullick, D.T. Golenbock, L.M. Stuart, E. Latz,
K.A. Fitzgerald, K.J. Moore, CD36 coordinates NLRP3 inflammasome activation by
facilitating intracellular nucleation of soluble ligands into particulate ligands in
sterile inflammation, Nat. Immunol. 14 (8) (2013) 812–820.
[68] M.T. Heneka, M.P. Kummer, A. Stutz, A. Delekate, S. Schwartz, A. Vieira-Saecker,
A. Griep, D. Axt, A. Remus, T.C. Tzeng, E. Gelpi, A. Halle, M. Korte, E. Latz,
D.T. Golenbock, NLRP3 is activated in Alzheimer's disease and contributes to pa-
thology in APP/PS1 mice, Nature 493 (7434) (2013) 674–678.
[69] J.Q. Shi, C.C. Zhang, X.L. Sun, X.X. Cheng, J.B. Wang, Y.D. Zhang, J. Xu, H.Q. Zou,
Antimalarial drug artemisinin extenuates amyloidogenesis and neuroinflammation
in APPswe/PS1dE9 transgenic mice via inhibition of nuclear factor-kappaB and
NLRP3 inflammasome activation, CNS Neurosci. Ther. 19 (4) (2013) 262–268.
[70] M. Schnaars, H. Beckert, A. Halle, Assessing beta-amyloid-induced NLRP3 in-
flammasome activation in primary microglia, Methods Mol. Biol. 1040 (2013) 1–8.
[71] V. Hornung, E. Latz, Critical functions of priming and lysosomal damage for NLRP3
activation, Eur. J. Immunol. 40 (3) (2010) 620–623.
[72] I. Hafner-Bratkovic, M. Bencina, K.A. Fitzgerald, D. Golenbock, R. Jerala, NLRP3
inflammasome activation in macrophage cell lines by prion protein fibrils as the
source of IL-1beta and neuronal toxicity, Cell. Mol. Life Sci. 69 (24) (2012)
4215–4228.
[73] M.S. Tan, J.T. Yu, T. Jiang, X.C. Zhu, L. Tan, The NLRP3 inflammasome in
Alzheimer's disease, Mol. Neurobiol. 48 (3) (2013) 875–882.
[74] K. Schroder, J. Tschopp, The inflammasomes, Cell 140 (6) (2010) 821–832.
[75] S. Mueller-Steiner, Y. Zhou, H. Arai, E.D. Roberson, B. Sun, J. Chen, X. Wang, G. Yu,
L. Esposito, L. Mucke, L. Gan, Antiamyloidogenic and neuroprotective functions of
cathepsin B: implications for Alzheimer's disease, Neuron 51 (6) (2006) 703–714.
[76] V.Y. Hook, M. Kindy, G. Hook, Inhibitors of cathepsin B improve memory and re-
duce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type,
but not the Swedish mutant, beta-secretase site of the amyloid precursor protein, J.
Biol. Chem. 283 (12) (2008) 7745–7753.
[77] N. Murphy, B. Grehan, M.A. Lynch, Glial uptake of amyloid beta induces NLRP3
inflammasome formation via cathepsin-dependent degradation of NLRP10,
NeuroMolecular Med. 16 (1) (2014) 205–215.
[78] M.H. Cho, K. Cho, H.J. Kang, E.Y. Jeon, H.S. Kim, H.J. Kwon, H.M. Kim, D.H. Kim,
S.Y. Yoon, Autophagy in microglia degrades extracellular beta-amyloid fibrils and
regulates the NLRP3 inflammasome, Autophagy 10 (10) (2014) 1761–1775.
[79] R. Abdullah, I. Basak, K.S. Patil, G. Alves, J.P. Larsen, S.G. Moller, Parkinson's
disease and age: the obvious but largely unexplored link, Exp. Gerontol. 68 (2015)
33–38.
[80] I. Stojkovska, B.M. Wagner, B.E. Morrison, Parkinson's disease and enhanced in-
flammatory response, Exp. Biol. Med. (Maywood) 240 (11) (2015) 1387–1395.
[81] E.C. Hirsch, T. Breidert, E. Rousselet, S. Hunot, A. Hartmann, P.P. Michel, The role
Q.-h. Shao et al.
of glial reaction and inflammation in Parkinson's disease, Ann. N. Y. Acad. Sci. 991
(2003) 214–228.
[82] C.C. Ferrari, M.C. Pott Godoy, R. Tarelli, M. Chertoff, A.M. Depino, F.J. Pitossi,
Progressive neurodegeneration and motor disabilities induced by chronic expres-
sion of IL-1beta in the substantia nigra, Neurobiol. Dis. 24 (1) (2006) 183–193.
[83] M.C. Pott Godoy, R. Tarelli, C.C. Ferrari, M.I. Sarchi, F.J. Pitossi, Central and sys-
temic IL-1 exacerbates neurodegeneration and motor symptoms in a model of
Parkinson's disease, Brain 131 (Pt 7) (2008) 1880–1894.
[84] M.T. Herrero, C. Estrada, L. Maatouk, S. Vyas, Inflammation in Parkinson's disease:
role of glucocorticoids, Front. Neuroanat. 9 (2015) 32.
[85] L. Alvarez-Erviti, Y. Couch, J. Richardson, J.M. Cooper, M.J. Wood, Alpha-synuclein
release by neurons activates the inflammatory response in a microglial cell line,
Neurosci. Res. 69 (4) (2011) 337–342.
[86] B. Winner, R. Jappelli, S.K. Maji, P.A. Desplats, L. Boyer, S. Aigner, C. Hetzer,
T. Loher, M. Vilar, S. Campioni, C. Tzitzilonis, A. Soragni, S. Jessberger, H. Mira,
A. Consiglio, E. Pham, E. Masliah, F.H. Gage, R. Riek, In vivo demonstration that
alpha-synuclein oligomers are toxic, Proc. Natl. Acad. Sci. U. S. A. 108 (10) (2011)
4194–4199.
[87] C.W. Olanow, P. Brundin, Parkinson's disease and alpha synuclein: is Parkinson's
disease a prion-like disorder? Mov. Disord. 28 (1) (2013) 31–40.
[88] D. Litteljohn, E. Mangano, M. Clarke, J. Bobyn, K. Moloney, S. Hayley,
Inflammatory mechanisms of neurodegeneration in toxin-based models of
Parkinson's disease, Park. Dis. 2011 (2010) 713517.
[89] S.V. More, H. Kumar, I.S. Kim, S.Y. Song, D.K. Choi, Cellular and molecular med-
iators of neuroinflammation in the pathogenesis of Parkinson's disease, Mediat.
160
International Immunopharmacology 49 (2017) 155–160
Inflamm. 2013 (2013) 952375.
[90] A. Gustot, J.I. Gallea, R. Sarroukh, M.S. Celej, J.M. Ruysschaert, V. Raussens,
Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease,
Biochem. J. 471 (3) (2015) 323–333.
[91] Z. Fan, M. Lu, C. Qiao, Y. Zhou, J.H. Ding, G. Hu, MicroRNA-7 enhances sub-
ventricular zone neurogenesis by inhibiting NLRP3/caspase-1 axis in adult neural
stem cells, Mol. Neurobiol. (2015).
[92] H.L. Roberts, D.R. Brown, Seeking a mechanism for the toxicity of oligomeric alpha-
synuclein, Biomol. Ther. 5 (2) (2015) 282–305.
[93] Y. Zhou, M. Lu, R.H. Du, C. Qiao, C.Y. Jiang, K.Z. Zhang, J.H. Ding, G. Hu,
MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neu-
roinflammation in the pathogenesis of Parkinson's disease, Mol. Neurodegener. 11
(2016) 28.
[94] H.J. Lee, S. Patel, S.J. Lee, Intravesicular localization and exocytosis of alpha-sy-
nuclein and its aggregates, J. Neurosci. 25 (25) (2005) 6016–6024.
[95] F. Martinon, Signaling by ROS drives inflammasome activation, Eur. J. Immunol. 40
(3) (2010) 616–619.
[96] D. Freeman, R. Cedillos, S. Choyke, Z. Lukic, K. McGuire, S. Marvin, A.M. Burrage,
S. Sudholt, A. Rana, C. O'Connor, C.M. Wiethoff, E.M. Campbell, Alpha-synuclein
induces lysosomal rupture and cathepsin dependent reactive oxygen species fol-
lowing endocytosis, PLoS One 8 (4) (2013) e62143.
[97] F. Shi, Y. Yang, M. Kouadir, Y. Fu, L. Yang, X. Zhou, X. Yin, D. Zhao, Inhibition of
phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-in-
duced NALP3 inflammasome activation in BV2 microglia, J. Neuroimmunol. 260
(1–2) (2013) 121–125.