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ARTICLE IN PRESSG ModelRR-547; No. of Pages 12

Ageing Research Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Ageing Research Reviews

jou rn al hom epage: www.elsev ier .com/ locate /ar r

eview

AMPs and neurodegeneration

ohn Thundyil a,∗, Kah-Leong Lima,b,c,∗

Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore, SingaporeDuke-NUS Graduate Medical School, Singapore, SingaporeDepartment of Physiology, National University of Singapore, Singapore, Singapore

r t i c l e i n f o

rticle history:eceived 1 August 2014eceived in revised form 6 November 2014ccepted 16 November 2014vailable online xxx

eywords:AMPseurodegenerationeuroinflammationRRsnflammasomes

a b s t r a c t

The concept of neuroinflammation has come a full circle; from being initially regarded as a controversialviewpoint to its present day acceptance as an integral component of neurodegenerative processes. Acloser look at the etiopathogenesis of many neurodegenerative conditions will reveal a patho-symbioticrelationship between neuroinflammation and neurodegeneration, where the two liaise with each otherto form a self-sustaining vicious cycle that facilitates neuronal demise. Here, we focus on damageassociated molecular patterns or DAMPs as a potentially important nexus in the context of this lethalneuroinflammation-neurodegeneration alliance. Since their nomenclature as “DAMPs” about a decadeago, these endogenous moieties have consistently been reported as novel players in sterile (non-infective)inflammation. However, their roles in inflammatory responses in the central nervous system (CNS),especially during chronic neurodegenerative disorders are still being actively researched. The aim ofthis review is to first provide a general overview of the neuroimmune response in the CNS within the
purview of DAMPs, its receptors and downstream signaling. This is then followed by discussions on someof the DAMP-mediated neuroinflammatory responses involved in chronic neurodegenerative diseases.Along the way, we also highlighted some important gaps in our existing knowledge regarding the roleof DAMPs in neurodegeneration, the clarification of which we believe would aid in the prospects ofdeveloping treatment or screening strategies directed at these molecules.
© 2014 Published by Elsevier B.V.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. DAMPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.1. Danger hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.2. Defining DAMPs and types of DAMPs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3. DAMP receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.3.1. Toll-like receptors (TLRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3.2. Receptor for advanced glycation end product (RAGE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3.3. The nucleotide-binding oligomerization domain receptors or NOD-like receptors (NLRs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.4. DAMP-mediated Inflammasome signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.5. NLRP1 inflammasome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.6. NLRP3 inflammasome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3. DAMPs in chronic neurodegenerative pathologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1. HMGB1 in chronic neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Please cite this article in press as: Thundyil, J., Lim, K.-L.,

http://dx.doi.org/10.1016/j.arr.2014.11.003

3.1.1. HMGB1 in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.2. HMGB1 in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1.3. HMGB1 in Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding authors at: Neurodegeneration Research Laboratory, National Neuroscel.: +65 63577520.

E-mail addresses: John LJ [email protected] (J. Thundyil), Kah Leong [email protected]

ttp://dx.doi.org/10.1016/j.arr.2014.11.003568-1637/© 2014 Published by Elsevier B.V.

DAMPs and neurodegeneration. Ageing Res. Rev. (2014),

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ience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore.

.sg, [email protected] (K.-L. Lim).

dx.doi.org/10.1016/j.arr.2014.11.003

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3.2. S100 proteins in chronic neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2.1. S100B in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2.2. S100B in PD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.3. Heat shock proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.4. Circulating DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.4.1. Mitochondrial DNA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.4.2. Cell free DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.5. Uric acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.6. Adenosine triphosphate (ATP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005. Closing thoughts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

The dramatic increase in average life expectancy is undoubtedlyne of the greatest wonders of the last century. With it however,as emerged the problem of age-related pathologies; many of theseffecting the central nervous system (CNS) (Cai et al., 2012; Formant al., 2004). In acute or chronic age-related CNS disorders, theost common denominator is the presence of a neurodegenerative

rocess (Amor et al., 2010). Although the etiology of the major-ty of these diseases remains unclear, it is generally accepted thathe degenerative process involves a myriad of shared pathologicalvents including oxidative stress, mitochondrial dysfunction, excit-tory toxicity, and protein aggregation (Campbell, 2004). Anothermportant neurodegenerative mechanism that has gained a lot ofcientific traction over recent years is neuroinflammation (Czirrnd Wyss-Coray, 2012).

In essence, neuroinflammation comprises of a dazzling tapestryf molecular events synchronized within the CNS that are acti-ated in response to noxious stimuli to help the system cope withhe deleterious insults (Minghetti, 2005). These events include thectivation of microglia and astrocytes, and the release of cytokines.owever, during the process of dealing with the harmful stimuli,euroinflammation may cause collateral damage and result in neu-odegeneration (Hohlfeld et al., 2007). Notably, proteinopathiesssociated with neurodegenerative disorders like Alzheimer’s dis-ase (AD) and Parkinson’s disease (PD) are capable of activatingeveral pro-inflammatory factors within the CNS (Cahill et al.,009). It is thus reasonable to surmise that the activation of such

nflammatory factors could contribute to the progression of the dis-ase by inciting an immune response (Amor et al., 2010; Benarroch,013). The fact that activation of the innate immune systems seemso be a common denominator among pathophysiologically diver-ent diseases like AD, PD and multiple sclerosis (MS), also ratifieshis proposition (Wilms et al., 2007; Zipp and Aktas, 2006). Furtherupporting this, studies conducted in animal models of neurode-eneration and post-mortem brain samples from patients sufferingrom neurodegenerative disorders often revealed the presence ofctivated microglia and the accumulation of inflammatory medi-tors at the lesion sites, which suggests a continuous crosstalketween the brain immune system and the injured neurons dur-

ng neurodegeneration (Griffin, 2006; Heneka and O’Banion, 2007).lthough microglial activation typically occurs as a response to con-

ain the initial triggering insult, their continued presence in largeumbers around the lesion areas may actually do more harm thanood to neuronal survival (Liu and Hong, 2003). Indeed, the removalf these chronically activated microglia was shown to prevent neu-ons from progressive degeneration (Liu and Hong, 2003). Further



echanistic studies revealed that the mere sustenance of microglian their activated states is sufficient for the progression of neu-onal death despite the absence of the initial triggering insult (Gaot al., 2011b). Corroborating with this, the degeneration of nigral

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dopaminergic neurons (i.e. neuronal population that are selec-tively lost in PD) in experimental mouse models of PD ensues longafter the clearance of the initial triggering insults [e.g. 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP)] amidst the persistentpresence of activated microglia (Gao et al., 2011a, 2011b). All theseobservations implicate microglial activation as a potential con-tributor of progressive neurodegeneration (Czirr and Wyss-Coray,2012). However, the pertinent question to ask is what regulatesthe sustained microglial activation in the absence of the initialtriggering insult? A reasonable conjecture is that certain inflam-matory factors being released by the dying neurons and/or activelysecreted from the activated microglia aid in maintaining the viciouscycle between activated microglia and the damaged neurons (Gaoand Hong, 2008; Gorman, 2008). In this regard, damage associatedmolecular patterns or DAMPs fit well into fulfilling such a role andmay represent an important cog in the wheel of chronic progressiveneurodegeneration.

2. DAMPs

2.1. Danger hypothesis

Although Matzinger coined the term “DAMP” in 2004, its con-cept was presaged about a decade back in the “danger hypothesis”(Matzinger, 1994, 1998, 2002). The hypothesis basically suggeststhat the body is capable of launching an immune reaction inresponse to both an infective stimuli as well as a sterile tissue injury(Land and Messmer, 2012). During a sterile (non-infective) tissueinjury, the damaged or dying cells release endogenous moleculesthat are regarded as “danger signals” by the host’s immune mecha-nisms. These signals in turn activate the immune system in a fashionanalogous to the microbe-associated molecular patterns (MAMPs),also known as PAMPs (pathogen-associated molecular patterns),that are released by pathogenic bacteria or viruses (Bianchi, 2007;Harris and Raucci, 2006). Thus, regardless of the source of tissueinjury, the immune system always stages a physiological inflam-matory response once it is engaged. This concept formed the basisof future developments in the field of DAMP-mediated neuroin-flammatory mechanisms.

2.2. Defining DAMPs and types of DAMPs

DAMPs are classically defined as nuclear or cytosolic moleculesreleased extracellularly in response to a non-infectious stimu-lus (sterile inflammation) that are then capable of triggeringand perpetuating an immune response in the body (Tang et al.,


2012). However, DAMPs can also act intracellularly. There is aconsiderable amount of heterogeneity between different DAMPmoieties, based on their cellular origin of release (epithelialor mesenchymal) and/or injured tissue. Protein molecules that

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Fig. 1. DAMP-mediated signaling. (A) Various DAMPs are released from differ-ent sub-cellular components of the neuron following injury to the neurons,which further activate their respective PRRs leading to downstream activationof pro-inflammatory cascades and augmenting neuroinflammation during chronicneurodegeneration. (B) Activation of various PRRs by DAMPs lead to downstreamactivation of inflammatory mediators; either via the MAP-kinase, NF�B or inflam-masome pathways, which promote cell death and contribute to neurodegenerativemTt

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echanisms. (C) Following a cue from DAMPs and consequent priming step ofLR activation the various molecular components (NLRs, Caspase-1, ASC) combineogether to form the multiprotein inflammasome complex.

erve as DAMPs include the intracellular proteins like heat-shockroteins, HMGB1 (high-mobility group box 1) and hyaluronragments (generated from the extracellular matrix following tis-ue injury). Non-protein DAMPs include Adenosine TriphosphateATP), uric acid, heparin sulfate and even DNA materials (Bianchi,007; Tang et al., 2012) (Fig. 1A).

.3. DAMP receptors



Typically, the receptors engaged by DAMPs include a groupf cellular receptors referred to as pattern recognition receptorsPRRs). PRRs serve as key molecular links between tissue injury andnflammation, by mediating downstream actions following their

PRESSh Reviews xxx (2014) xxx–xxx 3

activation by DAMPs engagement (Fig. 1A and B). Although theactivation of some of these PRRs is known to play protective rolesin host defense against danger, their aberrant activation can con-tribute in accentuating inflammation. Toll-like receptors (TLRs),Interleukin-1 receptor (IL-1R) and receptor for advanced glyca-tion end product (RAGE), the nucleotide-binding oligomerizationdomain receptors or NOD-like receptors (NLRs) are some of themore classical DAMP receptors (Burns et al., 2003; Okun et al., 2009;Ramasamy et al., 2009) (Fig. 1B). The TLRs and RAGE are membrane-bound surface receptors that sense extracellular DAMP moeities,whereas the NLRs are located intracellularly that sense intracellularDAMP signals. Some other examples of intracellular PRRs includethe RNA-sensing, RIG-I (retinoic acid-inducible gene I)-like recep-tors (RLRs; RLHs) or DNA-sensing, AIM2 (absent in melanoma 2)receptors.We discuss briefly a few of these PRRs below.

2.3.1. Toll-like receptors (TLRs)TLRs have been shown to induce and amplify the inflamma-

tory reaction in response to infective pathogens and endogenousmolecules alike. TLR2 and TLR4 signaling are known to mediateNuclear Factor Kappa B (NF-�B) activation initiated by HMGB1and serum amyloid A (SAA). The different TLR signaling pathwaysinvolved may cross talk at several levels, but all culminate in theactivation of NF-�B (Arroyo et al., 2011; Arumugam et al., 2009).

2.3.2. Receptor for advanced glycation end product (RAGE)RAGE is a multi-ligand receptor, belonging to the immunoglob-

ulin superfamily and is expressed on macrophages, neurons,endothelial cells and a variety of tumor cells. It interacts with avariety of DAMPs, including AGE (advanced glycation end prod-ucts), HMGB1, S100 proteins and �-amyloid (extracellular proteinaggregate associated with AD). Stimulation of RAGE induces theactivation of NF-�B and the mitogen-activated protein kinases(MAPKs) like extracellular signal-regulated kinases 1/2 (Erk1/2)and p38 MAPK. RAGE receptors have the unique ability to both initi-ate and perpetuate the inflammatory immune responses (Chavakiset al., 2003).

2.3.3. The nucleotide-binding oligomerization domain receptorsor NOD-like receptors (NLRs)

These are intracellular sensors of MAMPs and DAMPs that medi-ate innate immune inflammatory responses associated with cellstress. They are expressed by several immune and non-immunecells and are subdivided into different classes based on theirstructures and phylogenetic relationships. The nucleotide-bindingoligomerization domain, leucine rich repeat and pyrin domain con-taining receptors (NLRPs) belong to this family of receptor proteins(Lamkanfi and Dixit, 2009). NLR activation promotes the furtherdownstream activation of NF-�� or MAPK signaling pathways con-sequently leading to the production of cytokines and chemokines.In addition, they play a vital role in the formation of several inflam-masome complexes.

2.4. DAMP-mediated Inflammasome signaling

DAMP-mediated inflammasome signaling involves the down-stream activation of a group of multimeric protein complexesknown as inflammasome, which triggers the activation and cleav-age of the pro-inflammatory caspase-1, and consequent releaseof pro-inflammatory cytokines like Interleukin-1� (IL-1�) andInterleukin-18 (IL-18) . Structurally, the inflammasome comprises


of an inflammasome sensor moiety, an adaptor protein—apoptosis-associated speck-like protein containing a caspase recruitmentdomain (ASC), and caspase-1 (de Rivero Vaccari et al., 2014)(Fig. 1C). A vast majority of inflammasome sensors, which are

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ssentially cytosolic PRRs, belong to the members of the NLRP fam-ly (Vajjhala et al., 2012). These include the NLRP1, NLRP3, NLRP6,LRP7, NLRP12 or NLRC4 (Ting et al., 2008). Other inflammasome

ensors molecules include pyrin and HIN domain-containing pro-ein (PYHIN) family members, AIM2 and IFN�-inducible protein 16IFI16) and RIG-I (Proell et al., 2013). The adaptor protein ASC con-ists of two death-fold domains; the pyrin and the CARD (caspasectivation and recruitment domain) domains (Fernandes-Alnemrit al., 2007). The pyrin domain facilitates interaction with thepstream inflammasome sensor molecules. This interaction facil-

tates the assembly of ASC dimers into a large multimeric proteinFernandes-Alnemri and Alnemri, 2008). The CARD domain on thether hand, promotes the close positioning of ASC with monomersf pro-caspase-1 (the precursor molecule of active caspase-1),hereby initiating caspase-1 self-cleavage and the formation of thective caspase-1 (Proell et al., 2013). Active caspase-1 plays a vitalole in the initiation of pyroptosis, which is a rapid form of celleath following caspase-1 activation. Morphologically, the cellu-

ar attributes of pyroptosis bear semblance to those of apoptosissuch as DNA fragmentation) and necrosis (such as cell swellingnd rupture).

A range of substances that emerge during infections, tissueamage or metabolic imbalances can trigger the formation of

nflammasome complexes (Martinon et al., 2009). Once activated,he inflammasome sensor molecules binds to pro-caspase-1, eitheromotypically via its own CARD domain or via the CARD of thedaptor protein ASC (Chakraborty et al., 2010). Caspase-1 thenssembles into its active form consisting of two heterodimers with a20 and p10 subunit each. Once activated, caspase-1 proteolyticallyctivates a number of pro-inflammatory cytokines like pro-IL-1�nd pro-IL-18 (Freche et al., 2007). These potent pro-inflammatoryytokines are controlled by two important checkpoints: the tran-cription stage and its maturation/release stage (Dinarello, 2009).

hile the transcription of pro-IL-1� is mediated via NF-�Bnduction, pro-IL-18 is constitutively expressed and demonstratesncreased activity following cellular activation (de Rivero Vaccarit al., 2014) (Fig. 1B). Following their activation, the members of theL-1� cytokine family promotes the recruitment and the activationf other immune cells, such as neutrophils, at the site of infectionnd/or tissue damage (Lamkanfi et al., 2011). Thus, analogous tohe apoptosome that activates apoptotic cascades, the inflamma-ome activates an inflammatory cascade. The exact composition ofn inflammasome and its downstream activation is dependent onhe activator that initiates inflammasome assembly (Becker and’Neill, 2007). A descriptive mention of each of the inflamma-

ome cascade is beyond the scope of this review. However, a briefention about activation of NLRP1 and NLRP3 inflammasomes is

elevant in the context of chronic neurodegenerative pathologies.

.5. NLRP1 inflammasome

The neuronal NLRP1 inflammasome comprises of caspases- and -11, NLRP1, the adaptor protein ASC and the X-linked

nhibitor of apoptosis protein (XIAP). Assembly and activationf the NLRP1 inflammasome eventually leads to the maturationnd secretion of IL-1� and IL-18 (de Rivero Vaccari et al., 2008,009). Once secreted, these cytokines initiate inflammatory pro-esses throughout the CNS. These cytokines have been reportedo contribute to the pathology of different neurodegenerativeiseases such as AD and PD (Chiarini et al., 2006; Di Bona et al.,008; Koprich et al., 2008). However, the involvement of NLRP1ctivation in these pathologies still remains unclear. Interestingly,



awhinney et al. showed that aging induced increased expressionnd altered cellular distribution of critical components of theLRP1 inflammasome in hippocampal neurons. Increased levelsf inflammatory cytokines (IL-1� and IL-18), along with elevated

PRESSh Reviews xxx (2014) xxx–xxx

levels of different components of NLRP1 inflammasome includingcaspase-1, caspase-11 and XIAP, were found in the hippocampalprotein lysates of aged animals as compared to the younger ones.Furthermore, these changes also corresponded to age-related cog-nitive deficits in spatial learning in the aged animals (Mawhinneyet al., 2011). These findings suggest that aging-related activationof the NLRP1 inflammasome and its resultant inflammation maycontribute to age-related cognitive decline in the growing elderlypopulation. Conceivably, the inhibition of the heightened NLRP1inflammasome activity induced by the natural aging processmay be beneficial in impeding memory impairment. Overall, thefindings by Mawhinney and colleagues provided a good roadmapfor further investigations using age-related disease models.

2.6. NLRP3 inflammasome

The best characterized neuronal inflammasome is the NLRP3(also known as NALP3 and cryopyrin). NLRP3 oligomerization isactivated by a large number of stimuli. In addition, its activityhas been shown to be induced and/or increased by low intra-cellular potassium (K+) concentrations. Pore-forming toxins andATP-activated pannexin-1 may trigger K+ efflux and result in areduction of its intracellular level and/or grant access of toxins intothe cell to directly activate NLRP3. In addition, MAMPs like viruses,bacterial toxins, and most notably molecules associated with stressor danger, including crystalline and particulate substances such asmonosodium urate (MSU), alum, silica and asbestos can also acti-vate NLRP3 (Menu and Vince, 2011). NLRP3 activation is uniqueamong the NLRs in that its basal expression is not sufficient forinflammasome activation in resting cells. Its activation involvestwo distinct signals: The first signal includes the cellular primingand upregulation of NLRP3 and pro-IL-1� expression via Toll-likereceptor activation. The second ‘activation checkpoint’ results inthe assembly of the NLRP3 inflammasome, caspase-1 activation andIL-1� secretion (de Rivero Vaccari et al., 2014; Martinon et al., 2006;Pelegrin and Surprenant, 2007). Several mechanisms seem to playa role in the assembly of the NLRP3 inflammasome. These includemembrane damage leading to release of DAMPs, the efflux of intra-cellular potassium and the generation of reactive oxygen species(ROS) (Zheng et al., 2014).

Notably, several groups have reported higher expression of IL-1� in microglia surrounding �-amyloid plaques associated with AD(Apelt and Schliebs, 2001; Lue et al., 2001), suggesting the possi-ble involvement of NLRP3 in AD pathogenesis. The participationof NLRP3 inflammasome in these AD-related microglia was laterdemonstrated Halle et al. who also showed that NLRP3 activationleads to the production and secretion of IL-1� that in turn triggersfurther microgliosis resulting in an apparent vicious inflammatorycycle (Halle et al., 2008). An elegant study reported recently byHeneka et al. provided to date the clearest support for the role ofNLRP3 inflammasome in AD (Heneka et al., 2013). In this study, theauthors found that APP/PS1 mice (a model for AD), when crossedwith NLRP3-deficient (as well as capase-1 null) mice, are largelyprotected from the loss of spatial memory and other cognitivedeficiencies that are otherwise exhibited by APP/PS1 mice alone.Correlating with this improved phenotype, they also found thatNLRP3 deficiency reduces the �-amyloid load and at the same timeincreases the phagocytosis of �-amyloid by microglia. These find-ings suggest that blocking NLRP3 inflammasome activity may be arational therapeutic approach for AD.


3. DAMPs in chronic neurodegenerative pathologies

Several endogenous molecules serve as DAMPs in the CNS andmediate innate immune responses by engaging PRRs on local

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NS cells. These include high mobility HMGB1, HSPs, uric acid,hromatin, adenosine and ATP, galectins , thioredoxin, surfactantroteins A and D, hyaluronan, fibrinogen and aggregated, mod-

fied or misfolded proteins such as �-amyloid, alpha synuclein�-synuclein) and microtubule associated protein-tau, mutantuntigtin and mutant superoxide dismutase (SOD1). However, onlyome of them have been reported in the pathology of chroniceurodegenerative conditions. We discuss below some of theseolecules that are pertinent to CNS pathologies.

.1. HMGB1 in chronic neurodegeneration

The high-mobility group box (HMGB) proteins are non-histoneuclear proteins that act as DNA chaperones to regulate varioushromatin processes such as DNA transcription and replication.hey are so named so because of their high mobility in elec-rophoretic polyacrylamide gels. The HMGB family consists of three

embers – HMGB1, HMGB2 and HMGB3 – that share about 80%mino acid homology with each other. Amongst the three mem-ers, HMGB1 is the most highly conserved through evolution.he HMGB1 protein sequence is 99% identical among mammalianpecies with only two amino acid residues (out of 215) being substi-uted between its rodent and human versions. Structurally, HMGB1as two DNA-binding domains—the A-box (a.a. 1–79) and the B-ox (a.a. 89–163) and a highly acidic, repetitive C-terminal taila.a. 186–215). Although HMGB1 is a nuclear protein, it can beecreted into the extracellular milieu as a signaling molecule whenells are under stress as a cytokine mediator of inflammation. Theytokine-inducing part of the HMGB1 molecule comprises of therst 20 amino acids of the B-box domain (Ulloa and Messmer, 2006).MGB1 can also be found in the cytosol.

It may be fair to consider HMGB1 as the prototypical DAMPithin the CNS, as it is perhaps the most extensively studied DAMPithin the context of CNS pathologies. HMGB1 is ubiquitously

xpressed in neurons and glial cells (Fang et al., 2012). Function-lly, neural HMGB1 either serves as a nuclear factor importantor the regulation of DNA architecture or when secreted, as annflammatory factor or DAMP. The architectural roles of HMGB1re assumed early on during development, where its complex tem-oral and spatial distribution pattern within the CNS facilitateseurite outgrowth and cell migration. During adulthood however,MGB1 acts as a danger signal and promotes neuroinflamma-

ion following injury in the spinal cord or the brain (Fossati andhiarugi, 2007). To signal as an inflammatory mediator, HMGB1ust be released extracellularly. This extracellular release is pri-arily carried out by two principally different mechanisms: the

rst being an active secretion mode from living inflammatoryells or secondly being passively released from necrotic cells. Theassive release of HMGB1 acts as an early initiator of inflamma-ion whereas its active secretion via living cells like macrophageselps promote the inflammation. Hence, HMGB1 bears a uniquebility to both initiate neuroinflammation and also perpetuate itsrogress. Within the context of chronic neurodegenerative dis-rders, the roles of HMGB1 are still being explored continuallyDegryse and de Virgilio, 2003; Erlandsson Harris and Andersson,004; Gardella et al., 2002; Lotze and Tracey, 2005; Sun and Chao,005). We discuss the role of HMGB1 in a few of these diseaseselow.

.1.1. HMGB1 in AD



Consistent with the pathogenic role of HMGB1 in AD, the levelf the protein is significantly increased in both the cytosolic andarticulate fractions of AD brains (Takata et al., 2004). Further,MGB1 tends to co-localize with amyloid beta (A�) in senile


plaques associated with activated microglia. In rat hippocampiinjected with kainic acid and A�42 (i.e. the toxic form of A�),HMGB1 immunoreactivity is detected in senile plaques formed byA�42 and around dying neurons along with activated microglia.When these rats were co-injected with HMGB1 and A�42, HMGB1not only mediated the oligomerization of A�42, but also delayed itsclearance. This delay in clearance was the result of HMGB1 inducedinhibition of microglial A�42 phagocytosis. These results suggestthat HMGB1 promotes A� toxicity by causing a dysfunction inmicroglial phagocytosis and thereby, accelerating neurodegen-eration in these rats (Takata et al., 2004). Not surprisingly, miceinjected with HMGB1 intracerebroventricularly display impair-ments in encoding for long term memory (Mazarati et al., 2011).Interestingly, this phenotype may be rescued by the introductionof a TLR-4 antagonist in RAGE-deficient mice, suggesting thatTLR-4 and RAGE are responsible for HMGB1-mediated memoryimpairments. In another rodent model of AD (Tg2576 mice), Janget al. (2013) showed that deletion of the p35 gene, which codes foran activator of CDK5 (cyclin-dependent kinase 5), leads to highermortality rates and impaired spatial learning and memory at 6months of age. Immunohistochemical and biochemical analysesshowed a dramatic increase in the number of microglial cells in theregion of the hippocampus, which resulted in an elevated secretionof the soluble HMGB1 in response to A�. HMGB1 was found toaccelerate ER-mediated stress and consequent cell death in the p53KO/Tg2576 double mutant mice. Taken together, these findingssuggest that secretion of HMGB1 by activated microglia in responseto A� promotes neuronal death, synaptic destruction in thehippocampus, thereby leading to pronounced behavioral deficits.

3.1.2. HMGB1 in PD

Abnormal accumulation of �-synuclein (SNCA) filaments inLewy bodies is a neuropathological hallmark of PD and itssequestration into these protein aggregates has been shown to con-tribute to the degenerative process. HMGB1 preferentially bindsto aggregated �-synuclein and shows positive co-localization with�-synuclein in Lewy bodies from post-mortem PD brain samples(Erlandsson Harris and Andersson, 2004; Fang et al., 2012; Gaoet al., 2011b). Because of its known function in the nucleus, thesequestration of HMGB1 within �-synuclein aggregates suggeststhat �-synuclein could potentially disturb cellular gene expres-sion. As mentioned earlier, besides its nuclear functions, HMGB1also has roles to play in the cytosol and one of these is being aregulator of autophagy. Cytosolic HMG-B1 binds to the autophagyprotein Beclin1 and displaces Bcl-2 (whose interaction with Beclinserves to inhibit autophagy) (Tang et al., 2010). Interestingly,SNCA and its rare mutations have also been implicated as cul-prit proteins in autophagy dysregulation in PD. In a cultured cellmodel, Song et al., demonstrated that overexpression of bothwild-type (WT) and mutated SNCA (A53T) inhibits autophagy ina time-dependent manner (Song et al., 2014). Investigations intothe underlying mechanisms showed that SNCA binds to cyto-solic and nuclear HMGB1. This binding impaired the cytosolictranslocation of HMGB1, consequently blocking HMGB1-Beclin1binding and strengthening Beclin1–Bcl2 association, which leadsto autophagy inhibition. While siRNA knockdown of HMGB1 inthese cells inhibits basal autophagy, its overexpression restoresautophagy, thus suggesting that SNCA-induced impairment ofautophagy in PD may partly be dependent on HMGB1. On theother hand, HMGB1 obviously could promote neuroinflammation


in the PD brain. Attempts to examine the inflammatory mech-anisms incited by HMGB1 in animal models of PD revealed aninteraction between HMGB1 and Mac1, a microglial PRR. Fur-thermore, HMGB1–Mac1–NADPH oxidase signaling axis assisted

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hronic inflammation and progressive dopaminergic neurodegen-ration, hinting at the possibility that HMGB1 perhaps bridges theap between facilitating persistent neuroinflammation and medi-ting chronic neurodegeneration (Lindersson et al., 2004; Songt al., 2014; Zhang et al., 2013a, 2013b).

.1.3. HMGB1 in Huntington’s disease

In Huntington’s disease (HD) models, HMGB1 seems to pro-ect neurons against the toxicity of polyglutamine (polyQ) repeats.pparently, HMGB1 also exhibits chaperone-like activity. It directly

nteracts with polyQ repeats and reduces their propensity to aggre-ate (Min et al., 2013). Interestingly, proteome analysis of solubleuclear proteins prepared from neurons expressing mutant hun-ingtin or ataxin-1 (another polyQ containing protein) revealed aignificant reduction in the level of HMGB1 (and HMGB2). Fur-her analysis by immunohistochemistry demonstrated that theeduction of HMGB proteins occur in the nuclear region outside ofnclusion bodies in affected neurons. Importantly, ectopic expres-ion of HMGBs mitigated the pathology associated with polyQn both primary neurons and Drosophila polyQ models (Qi et al.,007).

Taken together, it appears that the role of HMGB1 in neurode-enerative diseases less than straightforward. In some instances, itould serve as a risk factor for the disease while in other instances itas protective functions. However, in all of these diseases, HMGB1as the capacity to assume a pro-inflammatory role. Understand-

ng the function of HMGB1 in different contexts would thus bemportant in positioning it as a potential therapeutic target foreurodegenerative diseases.

.2. S100 proteins in chronic neurodegeneration

S100 proteins, also known as calgranulins are small (10–12 kDa),alcium-binding proteins that are expressed exclusively in verte-rates. First identified by B.W. Moore in 1951, the S100 familyurrently consists of 24 members that are characterized intohree subgroups, i.e. those that only exert intracellular regulatoryffects, those that mainly exert extracellular regulatory effects andhe third that have both intracellular and extracellular functions.ence, these proteins are not just restricted to the intracellularilieu; rather they are also secreted and/or released extracellu-

arly in a paracrine or autocrine manner where they act to regulatearget cell functions. As alluded to earlier, these proteins are cal-ium sensors that modulate biological activity via calcium binding.hey are expressed in a diverse spectrum of tissues where they reg-late several physiological cellular functions such as cell growthnd differentiation, structural organization of membranes, dynam-cs of cytoskeleton constituents, and protection from oxidative cellamage, protein phosphorylation and secretion (Deloulme et al.,002; Donato et al., 2013; Heizmann et al., 2002; Schafer andeizmann, 1996). During pathological states, some of the S100 fam-

ly members are secreted extracellularly where they function aslarmins or DAMP factors that principally mediate functions of thennate immune systems. Examples include the S100A8, S100A9,nd S100A12, S100B that are secreted at sites of inflammationDonato et al., 2009).

With regards to pathological conditions in the CNS, informa-ion about the regulation of expression of most S100 proteins isragmentary. The S100B is one of the S100 family members thatre documented to exert its actions in the CNS. It is secreted or



eleased principally from astrocytes (Van Eldik and Wainwright,003). Depending on its concentration, it either has trophic oroxic effects on neurons, astrocytes and microglia. In the nanomolarange, S100B mediates neurotrophic actions protecting neuronal


cells against toxic stimuli by stimulating the p42/44 MAP kinaseand/or NF-�B-mediated upregulation of the anti-apoptotic Bcl-2gene (Sorci et al., 2010). On the other hand, micromolar doses leadto lethal effects on neuronal integrity via excessive ERK1/2 stimula-tion and ROS production and/or potentiation of neurotoxic effectsof �-amyloid, mediated by RAGE receptor activation. S100B alsopromotes inflammatory activities in astrocytes and microglia athigh-doses in a RAGE-dependent manner.

3.2.1. S100B in AD

Alteration in the level of S100B is associated with AD. In post-mortem AD brains, the expression of S100B correlates with the sitesof lesion, being highest in the most severely affected regions (VanEldik and Griffin, 1994). Consistent with this, S100B has been foundto associate with plaques. The level of S100B in serum or CSF is alsoan indirect indicator of the cognitive status of AD individuals. In thiscase, the relationship is inversely proportional, i.e. patients withhigher S100B levels exhibit lower cognitive scores (Chaves et al.,2010). Further supporting a relationship between S100B and ADis the identification of a single nucleotide polymorphism in S100Bgene (rs2300403) that is linked to impaired cognitive function andAD (Lambert et al., 2007). Thus, S100B appears to drive AD pathol-ogy. Supporting this, S100B null mice were demonstrated to exhibitenhanced spatial and fear memories as well as enhanced long-term potentiation (LTP) in the hippocampal CA1 region, whereasperfusion of hippocampal slices prepared from these mice withS100B reverses the levels of LTP (Kleindienst et al., 2005; Mori et al.,2010). Further, when the S100B gene is ablated in a mouse model ofAD, the double mutant mice exhibit regionally selective reductionsin plaque deposition (Roltsch et al., 2010). Although the mecha-nism by which S100B contributes to AD pathogenesis is not wellunderstood, there seems to exist a reciprocal relationship betweenthem whereby S100B expression promotes A� biogenesis and tauhyperphosphorylation and its expression is in turn enhanced byA� (Esposito et al., 2008). Notwithstanding this, it is likely that theprogression of AD is also accelerated by S100B-mediated neuro-inflammation. Notably, overexpression of S100B has been shownto accelerate AD-like pathology with enhanced astrogliosis andmicrogliosis (Businaro et al., 2006). Collectively, these studies sug-gest that S100B may be a relevant therapeutic target for AD. Indeed,pharmacological inhibition of S100B expression by arundic acidreduces plaque load and gliosis in the hippocampus and cortex ofTg2576 AD mice (Mori et al., 2006).

3.2.2. S100B in PD

As with the case in AD, increased S100B protein level is alsodetected in the brains of PD patients, especially in the degener-ating substantia nigra region, and also in the CSF (Sathe et al.,2012). MPTP, which causes neurological and pathological changescomparable to those observed in PD, increases S100B expres-sion in mice treated with the toxin. Conversely, mice ablated ofS100B gene exhibit protection against MPTP-induced neurotox-icity that is accompanied by a reduction in microgliosis as wellas reduced expression of RAGE and TNF� receptor (Sathe et al.,2012). Consistent with this, the culture medium of MPTP-treatedastrocytes reduces PC12 neuronal cell viability, an effect coun-teracted by an S100B neutralizing antibody. Although the abovestudies suggest that S100B is playing a detrimental role in PDpathogenesis, some studies have also shown that elevated S100Blevels can exert neuroprotective effects (Sorci et al., 2010). For


example, MPTP-treated mice injected with the antiepileptic drug,zonisamide (which improves PD symptoms) show enhanced S100Bexpression in astrocytes (Choudhury et al., 2011). This ameliora-tion of clinical signs of the disease was speculated to be due to an

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ugmented secretion of the neurotrophic S100B. Thus, the verdictegarding the role of S100B in PD remains open. The heterogeneityi.e. detrimental vs. beneficial) of S100B-mediated effects appearso be dependent on an S100-RAGE activity gradient, which is logi-al given that S100B effects are dependent on RAGE. So, any changen the activation intensities of RAGE, duration of RAGE stimulationnd/or different extents of S100B-induced upregulation of RAGExpression could influence the outcome of S100B-mediated effectsDonato et al., 2013; Sorci et al., 2011).

.3. Heat shock proteins

Heat shock proteins (HSPs) are molecular chaperones that facil-tate the proper folding and assembly of nascent polypeptides and

ediate the re-folding and stabilization of damaged polypeptides.he HSP family of proteins is classified into six major families:sp100, Hsp90, Hsp70, Hsp60, Hsp40 and small HSPs (sHSPs,.g., �B crystallin and Hsp27). The HSPs are constitutively andnducibly expressed in the nervous system and have been showno function intracellularly (Stetler et al., 2010). The role of HSPs asAMPs during neurodegeneration has not yet been fully elucidated.onetheless, there have been reports implicating them as DAMPs in

everal tissue injury models (Broere et al., 2011; Ganter et al., 2006;oCicero et al., 1999). In this regard, the roles of extracellular HSPs,ncluding Hsp72 (Gelain et al., 2011), Hsp27 (HSPB1), Hsp90 (HSPC),sp60 (HSPD) and Chaperonin/Hsp10 (HSPE) have been shown toe particularly relevant in sepsis. These studies demonstrated thextracellular release of HSPs from damaged or stressed cells prop-gated local “danger signals”, thereby activating stress responserograms in surrounding cells (Adachi et al., 2009; Giuliano et al.,011). However, these reports have been met with a fair share ofkepticism by the community; the reason being that HSPs werehown to bind to several MAMPs and enhanced TLR ligand stimu-ation, making the interpretation of published results inconclusiveBroere et al., 2011; Chen and Nunez, 2010; Habich et al., 2005;sterloh et al., 2007; Warger et al., 2006). In addition, even theure forms of HSP preparation showed the presence of microbialroducts. The depletion of microbial products from HSP prepara-ions reduced or completely abolished HSP-induced inflammatoryesponses thus weakening the role HSPs acting as DAMPs (van Edent al., 2012).

.4. Circulating DNA

Several studies have previously demonstrated baseline levelsf plasma DNA in normal, healthy populations, albeit at very lowevels (Jylhava et al., 2011). The level of circulating cell-free (cf-NA) and mitochondrial DNA is however elevated in the plasma ofritically ill patients, including those with sepsis, myocardial infarc-ion, trauma and even chronic conditions like cancer. Increasedlasma levels of mitochondrial and cf-DNA seem to be inherently

inked with underlying systemic inflammatory conditions, oxida-ive stress or robust tissue damage (Jylhava et al., 2012; Pinti et al.,014). Potentially, they might also play a role in aging and neurode-eneration.

.4.1. Mitochondrial DNA

Intra-mitochondrial components, including mitochondrial DNAmt-DNA), N-formyl peptides, and lipids such as cardiolipin, cane released extracellularly, which then enter the blood flow to



ct as DAMP agents, triggering the same pathways that respondo MAMPs, thereby causing inflammation (Zhang et al., 2010b).

t-DNA can bind TLR-9 and activate its downstream pathway.any studies have previously shown that immune cells, including


monocytes and granulocytes, express TLR-9, and that triggeringof TLR-9 in these cells by mt-DNA, induces the release of typeI IFNs and TNF-�, through the activation of IRAK-1, IRAK-2, andIRAK-4 and the phosphorylation of p38 MAP kinase (Hauser et al.,2010; Manfredi and Rovere-Querini, 2010; Zhang et al., 2010a).During aging, the human body is progressively exposed to avariety of antigens. Consequently, the burden to cope up withthis life-long antigenic stress accumulates on the body’s defensemechanism—the immune system (Giunta, 2006). The immunesystem in turn, responds to this aging-related antigenic stressby initiating a chronic low-grade inflammation characterized bymildly elevated plasma levels of pro-inflammatory cytokines. Thisold-age related inflammatory status is now being recognized as“inflamm-aging” (Zheng, 2014). In order to investigate whethercirculating mt-DNA could significantly contribute to the onset ofinflamm-aging in human subjects, Pinti et al. evaluated mt-DNAcontent was evaluated in plasma samples of 800 Caucasian sub-jects aged between 1 and 104 years (Pinti et al., 2014). Theyalso evaluated a possible genetic correlation to the circulatinglevel of mt-DNA, by comparing their levels in a large cohort ofultra-nonagenarian siblings. Their results showed that mt-DNAplasma levels increased gradually after the fifth decade of life,indicating an age-dependency (Pinti et al., 2014). In the ultra-nonagenarian cohort, mt-DNA values highly correlated withinsibling pairs, highlighting a possible role of genetic backgroundin controlling the levels of circulating mt-DNA. Further evaluationrevealed a strong correlation between plasma levels of mt-DNAand pro-inflammatory cytokines in older subjects and 90+ sib-lings. The subjects with the highest mt-DNA plasma levels had thehighest amounts of TNF-�, IL-6, RANTES, and IL-1R; while the sub-jects with the lowest mt-DNA levels had the lowest levels of thesame cytokines (Pinti et al., 2014). Tests to evaluate the capac-ity of mt-DNA to stimulate the production of pro-inflammatorycytokines in vitro showed that monocytes stimulated with mt-DNAconcentrations similar to the highest levels observed in subjects,secrete increased levels of TNF-�, thereby suggesting that mt-DNA can modulate the production of pro-inflammatory cytokines.Investigations into the suspected PRR mediating these inflamma-tory signals showed that mt-DNA was able to trigger the pathwaydownstream of TLR-9 and mediate the release of TNF-�. Thus,mitochondria not only participate in danger signaling inside thecell, but are also a major source of DAMP molecules able toactivate an innate immune response. These findings suggest anage-dependent increase in circulating mt-DNA, which can also besignificant contributor toward the low-grade, chronic inflamma-tion observed in elderly people. Moreover targeting TLR-9 receptorsignaling and/or interfering with soluble mitochondrial DAMPscould perhaps reduce harmful immune activation during aging-related pathologies. At the same time, it is also attractive tospeculate that mt-DNA-mediated inflammation may trigger neu-rodegeneration in the brains of susceptible elderly individuals.Supporting this, Mathew et al. recently demonstrated that primaryastrocytes with oxidant-initiated degraded mitochondrial polynu-cleotides, which they termed DeMPs, induce the production ofpro-inflammatory cytokines and the activation of the inflamma-some. They further showed the presence of DeMPs in human CSFand plasma and that DeMPs are produced in response to oxidativestress (Mathew et al., 2012).

3.4.2. Cell free DNA

Circulating cell-free DNA (cf-DNA) is currently thought to arise


from apoptotic or necrotic cells and may thus reflect systemicinflammatory conditions or tissue damage. Interestingly, a studyby Jylhävä revealed that aging is associated with quantitative andqualitative changes in circulating c-f DNA (Jylhava et al., 2012).

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hey observed that the concentration of cf-DNA is significantlyigher in aged individuals (>90 years) as compared to youngerontrols (22–37 years) and that the older group tends to display aragmented pattern of low molecular weight cf-DNA compared toheir younger counterparts, whose cf-DNA was intact and assumed

high molecular weight appearance. More recently, the sameroup found an association between cf-DNA and inflammation inhe nonagenarians but not in the young controls, suggesting thatf-DNA might aggravate immunoinflammatory activity in elderlyndividuals (Jylhava et al., 2013). Mechanistically, cf-DNA can acts a DAMP by activating TLR and non-TLR receptors. TLR-9 actss a ubiquitous receptor for endocytosed DNA. Intracellular sig-al transduction of the DNA-induced TLR9-pathway is mediatedhrough the MyD88 and a series of activation events, resulting inn IFN-regulatory factor 7 (IRF7)-mediated type-I IFN response, orn NF-kB or mitogen-activated protein kinase-dependent cytokinend chemokine production (Barbalat et al., 2011). AIM2 is anotherRR capable of recognizing cytoplasmic DNA, independent of TLR-ignaling that can lead to caspase-1 mediated pyroptosis. Howeverhis list of DNA sensing molecules is still expanding with manyncharacterized DNA sensing PRRs and downstream pathways stillaiting to be discovered. Given the presence of a damaged BBB in

hronic neurodegenerative conditions, it may be quite possible thathe DNA material release from dead neuronal cells may perhapsnd its way into systemic circulation and incite an inflammatoryeaction by binding and activation of PRRs (McRae and Dahlstrom,992; Su and Federoff, 2014). The elevated cf-DNA concentrations

n the blood also increase the viscosity of blood and could oftentimulate autoimmune response—a phenomenon often encoun-ered in aged individuals (Ellinger et al., 2012; Kohler et al., 2009;yle et al., 2010). Future studies should clarify the role of cf-DNA ineurodegeneration.

.5. Uric acid

Uric acid is the final metabolic product of purine metabolismn humans. Normally, uric acid disposal occurs via the kidneys ands excreted in urine. The lack of uricase enzyme makes it impossi-le for humans to oxidize uric acid to the more soluble compoundllantoin. Thus hyperuricemia, defined as high levels of blood uriccid, has been increasingly linked with pathology of several sys-emic diseases and can be detrimental to the body (Kutzing andirestein, 2008). For example, uricase gene deficient mice have a0 fold increase in the serum uric acid level, and are found to haverate nephropathy with infiltration of plasma cells, lymphocytes,nd macrophages (Jin et al., 2012). Additionally, monosodium urateMSU) crystals formed in the blood, as a result of uric acid lev-ls exceeding 6.8 mg/dL, have been associated with inflammatoryathologies like gout, and several vascular diseases. MSU crys-als activate the TLRs, which then activate NLRP3 inflammasomeJin et al., 2012). MSU has been shown to interact with TLR2 andLR4. Using antibody-blocking and transfection approaches, MSUas shown to interact with TLR2 on chondrocytes to induce nitric

xide (Liu-Bryan et al., 2005b). MSU mediated TLR2/TLR4 activa-ion also led to IL-1� production (Liu-Bryan et al., 2005a). MSU alsoriggers neutrophil activation and further produces immune medi-tors, which lead to a pro-inflammatory response. Hence, uric acidrystals can acts as DAMP, mediating an inflammatory response ineveral cardiac, kidney and joint pathologies (Jounai et al., 2012).

However, hyperuricemia also seems to have beneficial effects inhe nervous system, as evidenced by favorable outcomes observed



n some neurological diseases (Romanos et al., 2007). Reducedevels of serum uric acid have been associated with PD, HD, and

S occurrence. Annanmaki et al. (2007, 2008, 2011) showed thatatients with PD have significantly lower plasma uric acid levels


when compared with matched controls. In addition, men showed asignificant inverse correlation between uric acid levels and diseaseduration, with lower levels associated with longer duration of PD(Andreadou et al., 2009). These results suggested that patients withhyperuricemic levels seen in gout may perhaps have a protectiveeffect in PD. In a prospective case-controlled study to determinethe association between gout and the risk of developing PD, Alonsoet al. (2007), Alonso and Sovell (2010) found that individuals with ahistory of gout have significantly lower risk of developing PD thanthose without a history of gout. However, this finding was only sig-nificant for men, but not for women. De Vera et al. later publishedthat over an 8-year median follow up, there was a 30% reductionin the risk of developing PD in both male and female patients witha history of gout, independent of age, prior co-morbid conditions,and non-steroidal anti-inflammatory drugs (NSAIDs) or diuretic use(Alonso et al., 2007; Alonso and Sovell, 2010; De Vera et al., 2008). Ina 6-OHDA PD model in SH-SY5Y cells, Huang et al. (2012) showedthat the toxin induced cell injury is attenuated by uric acid. Theunderlying mechanisms may involve the up-regulation of Akt andthe reduction of GSK-3� activity. Similarly, Auinger et al. (2010)also found an association between higher serum uric acid levelsand slower HD progression (Auinger et al., 2010). In addition, therewas a trend of decreased worsening of motor function with increas-ing uric acid levels, hinting that uric acid may aid as a therapeutictarget for the slowing of the motor component of HD progression.However, cognitive, behavioral, and neuropsychological functionsdid not correlate to uric acid levels.

3.6. Adenosine triphosphate (ATP)

ATP is a purine base that mediates almost all physical responsessuch as glucose metabolism, muscle contraction, biosynthesis, andmolecular transfer within the cell. Despite its roles as an almostindispensible intracellular molecule, ATP released extracellularlyfrom dead or injured cells can trigger the activation of NLRP3 andcaspase-1 (Communi et al., 2000). In addition, other ion chan-nel molecules, namely, P2X7 and pannexin-1, can also induceextracellular ATP-mediated caspase-1 activation following IL-1�maturation (Ferrari et al., 2006; Kanneganti et al., 2006). Althoughextracellular ATP has been suggested to act as a DAMP molecule,there is no however correlation between high amounts of extra-cellular ATP acting as DAMPs under physiological conditions invivo. Eckle et al. (2007) suggested that most extracellular ATPmay undergo hydrolysis by ectonucleotidases. Notwithstandingthis, extracellular ATP per se is toxic for primary neuronal as wellorganotypic CNS cultures. Additionally, P2 receptors can also medi-ate and aggravate hypoxic signaling in many CNS neurons. Takentogether, there is a potential role for extracellular ATP to promoteneurodegeneration via its DAMP-like functions although this non-conventional function of ATP needs to be examined in more depth.

4. Discussion

Normal aging is known to lead to the development of a chroniclow-grade inflammatory state within the body (Noyan-Ashrafet al., 2005). Even the immune privileged brain is not spared ofthis age-associated inflammatory phenomenon, which is likely toprecipitate or augment neurodegeneration in susceptible elderlyindividuals. Clinical studies in elderly patients suffering from infec-tions revealed an increase in the occurrence of deliriums anddevelopment of dementia (Wofford et al., 1996). These results point


toward an on-going low level inflammatory response in the agedbrain that tends to accentuate following an antigenic stimulus(involving MAMPs in the case of an infective state). The conse-quent amplified production of inflammatory molecules in the brain

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ig. 2. DAMPs—A nexus in neuroinflammation–neurodegeneration liason. Following itshich help in sustaining microglial activation and thereby perpetuating the progre

ay then result in frank neuronal loss leading to cognitive anderhaps other neurological impairments (Barrientos et al., 2006).n analogy to this inflammatory process could perhaps be applied

o delineate the contribution of DAMPs during chronic neurode-enerative states. Whilst the ageing process primes the microgliaia a mild but sustained inflammatory stimulus, an exposure totressors, either in the form of environmental toxins or mutations-nduced protein aggregates could then trigger them to launch aotent inflammatory onslaught that could prove detrimental toeuronal health in the afflicted brain regions (Golde et al., 2013;an et al., 2014).

The common pathological hallmark of a majority of the neurode-enerative conditions is the abnormal accumulation of proteins,ome of which can operate as endogenous danger signals or DAMPs.dditionally, other DAMP moieties like HMGB1, S100B, mt-DNA arelso elevated in AD and PD and also MS (Donato et al., 2013; Gaot al., 2011b; Heizmann et al., 2002). The majority of these DAMPsncite the release of pro-inflammatory cytokines like IL-1� and IL-8, thereby further contributing to the neurodegenerative process.

L-1� is synthesized and secreted both, by neuronal and glial cellsLechan et al., 1990). These cells also express PRRs like RAGE, NODsnd NLRPs. In addition, ASC, caspase-1 and caspase-11 are presentn astrocytes, oligodendrocytes and microglial cells (Mawhinneyt al., 2011). Thus, neurons and glial cells possess all the compo-ents that could facilitate their engagement in a positive feedbackechanism to potentiate pro-inflammatory responses during neu-

odegenerative conditions. This mechanism could be initiated withhe release of endogenous proteins and cytokines by dead neu-ons in the affected regions, which could then engage PRRs oneighbouring neurons and microglial cells to incite activation of

nflammasome complexes and cause a further release of IL-1� andL-18 (Fig. 2).

Although a number of reports suggest the involvement ofnflammasomes (NLRP3 and NLRP1) in chronic neurodegeneration,everal important questions still remain unanswered (Mawhinneyt al., 2011; Tan et al., 2013). Firstly, how many inflammasome



omplexes exist within the CNS and what are their specific roles?econdly, pertaining to their molecular mechanisms of activa-ion; how is the assembly of different inflammasome complexesriggered during neurodegeneration? Furthermore, is there any

e from injured neurons, DAMPs activate the PRRs on adjacent neurons and microgliaeuroinflammation-neurodegeneration cycle.

crosstalk between different inflammasome complexes? Anotherfacet of DAMP-mediated neuroinflammation is the concept ofpyroptosis, which is a form of cell death that is uniquely dependenton caspase-1. Although reports about neuronal death via pyroptosisin vivo are rare, its occurrence in these degenerative states cannotbe ruled out. This is because the activation of caspase-1 has beenshown in models of chronic neurodegeneration (Friedlander, 2003).Moreover, pyroptotic cell death leads to osmotic swelling and sub-sequent rupture of the cytoplasmic membrane that result in therelease of cytoplasmic contents (Fernandes-Alnemri et al., 2007).This then could perhaps be one of the mechanisms underlying therelease of DAMPs in the brain during chronic neurodegeneration.Thus, it is important to investigate the role of caspase-1 in thecontext of chronic neurodegeneration. As mice deficient only forcaspase-1 are now available, the specific contribution of caspase-1 to chronic neuroinflammation can now be addressed to someextent. However, owing to the obvious differences between miceand men, particularly at the immunologic level, knock down studieswith human (primary) cells could be more relevant in the analy-sis of the function of caspase-1 in humans. Finally, it is not clear atpresent whether all the protein aggregates functions as DAMPs and,if so, do they all behave in similar or distinct fashions? Addressingthese gaps in our understanding could perhaps facilitate in iden-tifying receptor targets and/or downstream mechanisms that maybe a common feature of the downstream degenerative cascades inmultiple CNS proteinopathies, which may in turn lead to the devel-opment of common therapeutic targets for multiple CNS disorders.

5. Closing thoughts

In recent years, much has been learnt about the roles of DAMPsin mediating immune responses during acute and chronic neu-rodegenerative pathologies. While the basic understanding of theseinnate immune activators in neurodegeneration is growing, theirclinical implications in the context of human patients are stilllargely unclear. It is perhaps intuitive to devise ways to integrate


this newfound knowledge and understanding regarding DAMPsinto clinical applications pertaining to chronic neurodegenera-tive pathologies. In this regard, understanding the implicationsof DAMP-mediated neuroinflammation could provide us with

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aluable hints at exploring possible diagnostic and therapeuticpproaches aimed at mitigating the progress of neurodegenerativeathologies.

The mechanistic requirement for intracellular endogenous moi-ties to be released extracellularly in many cases in order tounction as DAMPs provides important opportunities to probe theirotential as biological markers in neurodegenerative pathologies.owever, the non-specificity of these moieties with regards to

he CNS dampens any prospects of developing these DAMPs aserum bio-markers of chronic neurodegenerative pathologies. Fornstance, S100B, which is normally found in pM amounts in humanerum under normal physiological state, is elevated in AD as well asther non-neurological clinical conditions such as cardiac ischemiand extracerebral infections. A similar problem is also seen withhe use of HMGB1, uric acid, cell-free and mitochondrial DNA asiomarkers of neurodegeneration. While their elevated levels are

ndicative of an inflammatory phenotype, they do not specificallymply a neurodegenerative state (or a specific neurodegenerativeisorder). This lack of specificity could make the interpretation oflevated levels of DAMPs rather confounding, especially in patientsaving multiple systemic pathologies. Perhaps their incorpora-ion with other specific disease markers along with a more robustssessment and large patient cohorts may increase their effectivese as a diagnostic marker.

Aside from being biomarkers, DAMPs may also be positioneds disease targets. Accumulating evidences show that therapeutictrategies that modulate the expression of DAMPs and its down-tream signaling could aid in the treatment of neurodegenerativeiseases. Small molecule inhibitors or antibodies against circulat-

ng mt-DNA, extracellular DAMPs, or microglial PRRs may proveo be novel strategy in therapy directed toward neurodegenerativeiseases. However, the majority of these DAMPs tend to assume theJekyll and Hyde” roles within the CNS. Whilst they mediate sev-ral physiological cellular functions inside the cell, they assume aytokine-like character with multiple signaling properties (for e.g.MGB1, S100B) upon their release into the extracellular milieu. Thehallenge would be to develop specific and powerful inhibitors withn acceptable degree of selectivity and pharmacokinetic profile sohat only the harmful extracellular DAMPs are targeted. Anotherchilles’ tendon in deriving effective therapies is the impact of

hese drugs in modulating the innate immune response. The innatemmune systems are primarily activated as a defense mechanism.oo much or too little modulation of these responses could prove toe counterproductive in terms of long-term side effects in patients.ence, a detailed knowledge of DAMP-mediated signaling mech-nisms is required to judge the timing and degree of interventiono that maximum hit rate could be achieved with minimum sideffects.

cknowledgements

This work was supported by grants from the National Medicalesearch Council-CBRG (0049-2013) and the Translational Clinicalesearch Programme in Parkinson’s disease. We thank Ms. Hangiting for illustrations.

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DAMPs and neurodegeneration