Tissue transglutaminase in Alzheimer\'s disease: involvement in pathogenesis and its potential as a therapeutic target

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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-132492 IOS Press

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Tissue Transglutaminase in Alzheimer’s Disease: Involvement in Pathogenesis and its Potential as a Therapeutic Target

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Micha M.M. Wilhelmusa,∗ , Mieke de Jagera , Erik N.T.P. Bakkerb and Benjamin Drukarcha

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of Anatomy and Neurosciences, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands b Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands

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Abstract. Protein misfolding and the formation of stable insoluble protein complexes by self-interacting proteins, in particular amyloid-␤ and tau protein, play a central role in the pathogenesis of Alzheimer’s disease (AD). Unfortunately, the underlying mechanisms that trigger the misfolding of self-interacting proteins that eventually results in formation of neurotoxic dimers, oligomers, and aggregates remain unclear. Elucidation of the driving forces of protein complex formation in AD is of crucial importance for the development of disease-modifying therapies. Tissue transglutaminase (tTG) is a calcium-dependent enzyme that induces the formation of covalent ␧-(␥-glutamyl)lysine isopeptide bonds, which results in both intra- and intermolecular protein cross-links. These tTG-catalyzed intermolecular cross-links induce stable, rigid, and insoluble protein complexes, whereas intramolecular cross-links change the conformation of proteins. Inhibition of tTG-catalyzed cross-linking counteracts the formation of protein aggregates, as observed in disease-models of other protein misfolding diseases, in particular Parkinson’s and Huntington’s diseases. Although data of tTG activity in AD models is limited, there is compelling evidence from both in vitro and postmortem human brain tissue of AD patients that point toward a crucial role for tTG in the pathogenesis of AD. Here, we review these data on the role of tTG in the initiation and development of protein aggregates in AD, and discuss the possibility to use inhibitors of the cross-linking activity of tTG as a new therapeutic approach for AD.

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Accepted 23 February 2014

Keywords: Alzheimer’s disease, amyloid-␤, cerebral amyloid angiopathy, crosslinking, neurofibrillary tangles, senile plaques, therapy, tissue transglutaminase

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INTRODUCTION

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Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the most common form of dementia. Although a great leap has been made in identifying genes involved in early-onset AD and ∗ Correspondence

to: Micha M.M. Wilhelmus, Department of Anatomy and Neurosciences, VU University Medical Center, Neuroscience Campus Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Tel.: +31 20 4448103; Fax: +31 20 4448100; E-mail: [email protected].

unravelling the biological mechanisms of AD, only limited progress has been made in the development of truly disease-modifying treatments. It goes without saying that novel therapeutic targets and agents are of crucial importance for the AD field. Almost all current trials are based on the removal and/or prevention of accumulation of neurotoxic protein multimers and aggregates in AD. Unfortunately, however, the mechanisms that drive the formation of these multimers and aggregates remain largely unknown. Senile plaques (SPs), neurofibrillary tangles (NFTs), and cerebral

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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treatment with the competitive tTG-inhibitor, cystamine, inhibition of ␣-synuclein aggregate formation was observed [9]. In cell models of another proteininclusion neurodegenerative disease, i.e., Huntington’s disease, similar effects were observed upon tTG inhibition [10, 11]. In addition, in Huntington’s disease mouse models, cystamine treatment resulted in improved motor function and increased survival compared to non-treated mice [12, 13]. Together, these data strongly support the notion that tTG cross-linking activity is directly linked to protein oligomerization and aggregation, and that inhibition of tTG activity might be a potential therapeutic target to counteract the formation of neurotoxic oligomers and aggregates in these neurodegenerative diseases. In addition to the findings in Parkinson’s and Huntington’s diseases, the potential importance of cross-links induced by tTG in AD pathogenesis was already noted in the early nineteen eighties [14]. Since then, evidence for a role of tTG in the pathogenesis of AD has been mounting [15, 16]. Surprisingly, however, despite the growing body of evidence that supports the idea that tTG plays a key role in protein aggregation in AD, unlike Parkinson’s and Huntington’s diseases, studies on the effects of inhibition of tTG in AD models, either cellular or animal, are very limited. This review intends to provide an overview of the current knowledge on the role of tTG in the initiation and development of neurotoxic oligomers and aggregates in AD, and discusses the possibility to use inhibitors of tTG cross-linking activity as therapeutic agents.

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amyloid angiopathy (CAA) [1] are the main pathological brain lesions defining AD. Both SPs and CAA primarily comprise extracellular deposition of aggregated amyloid-␤ (A␤) protein, a 4 kDa proteolytic cleavage product of the amyloid-␤ protein precursor. In SPs, neurotoxic A␤ oligomers and aggregates are formed and deposited in the brain parenchyma, whereas in CAA, A␤ accumulates in the outer portion of the media of brain vessels, leading to degeneration of both cerebrovascular cells and ultimately neurons. NFTs are intraneuronal inclusions in the cytoplasm of the neuron composed of paired helical filaments. These filaments consist of hyperphosphorylated bundles of the microtubule-binding protein tau [2], which is involved in microtubule stabilization. For reasons not well-understood, the tau protein is hyperphosphorylated in neurons in AD, resulting in abnormal self-polymerization and aggregation of tau, leading to disturbances in microtubule dynamics [3, 4]. In this manner, hyperphosphorylated tau aggregation leads to destabilization and disruption of cytoskeleton integrity and thus, cell function and viability [5]. Despite the well-characterized pathology underlying AD, current symptomatic therapies and recent trials designed to counteract and/or remove aggregate formation and deposition in AD patients have met with little success. Tissue transglutaminase (tTG) is a member of the transglutaminase protein family (EC 2.3.2.13) of which there are nine encoded in the human genome. tTG is a calcium-dependent enzyme that catalyzes several reactions, including the formation of (␥-glutamyl)polyamine bonds [6], the deamidation of protein substrates [7], and the formation of covalent ␧-(␥-glutamyl)lysine isopeptide bonds, which result in both intra- and intermolecular protein cross-links (Fig. 1). tTG-catalyzed intermolecular cross-links induce stable, rigid, and insoluble protein complexes [8], whereas intramolecular cross-links change the conformation of proteins (Fig. 1). It is the formation of stable protein complexes which are induced by self-interacting proteins that play a central role in the pathogenesis of a number of neurodegenerative diseases. Thus, inhibition of tTG-catalyzed cross-linking of proteins involved in neurodegenerative diseases might be a potential therapeutic strategy to counteract the disease process. Interestingly, in Parkinson’s disease models, in which the ␣-synuclein protein aggregates and forms neurotoxic inclusions, inhibition of tTG showed a direct inhibitory effect on the formation of ␣-synuclein aggregates [9]. Conversely, in cells transfected with both tTG and ␣-synuclein, enzymatic tTG activity induced aggregation of ␣-synuclein. After

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CURRENT AND EMERGING THERAPIES FOR AD The major current therapeutic strategy for AD is centered around the “cholinergic hypothesis” described in 1982 [17], which resulted in the introduction of several cholinesterase inhibitors, i.e., donepezil, rivastigmine, and galantamine, for use in the clinic today. Treatment with cholinesterase inhibitors results in a small but significant improvement in cognitive function and overall clinical condition. In addition to cholinesterase inhibitors, the N-methyl-D-aspartate (NMDA) blocker memantine is used as a therapeutic agent in AD. The underlying basis for this treatment is the alleged excitotoxicity of the neurotransmitter glutamate in AD, a common process underlying neuronal cell death in neurodegenerative diseases [18]. Exocitotoxicity results from overactivation of the NMDA receptor, leading to excessive intracellular influx of calcium

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Phase III as they caused clinical worsening and other safety concerns [27, 28], or are still in earlier phases of development [29].

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and subsequent neuronal cell death [19]. Preclinical studies have shown that blockade of the NMDA receptor by memantine inhibits A␤-induced neurotoxicity [20–22]. Clinical studies show that memantine reduces the incidence of clinical worsening in key symptomatic domains in moderate to severe AD [23]. Thus, although all above-described therapeutic strategies have some positive symptomatic effects on AD patients, they do not seem to modify the course of the disease and/or alter the rate of progression of neurodegeneration in AD. For this purpose, new therapeutic strategies are required that modify the processes underlying the disease. Within this context, an important category of emerging therapies for AD are the immuno-based therapies that are designed to remove A␤ from the brain, by either passive immunization, administration of intravenous immunoglobulins, or active immunization schemes. Although these therapeutic strategies appeared promising in preclinical studies and early stage clinical trials, so far, none of the antibody-based therapies where able to meet the primary endpoints of improvement in cognition and global functioning in large scale clinical studies [24–26]. Apart from therapies targeting the removal of A␤ from the brain are those that focus on decreasing A␤ production. These therapies are designed to restrain the generation of A␤ by inhibiting ␤- and ␥-secretases that cleave A␤ from its precursor. Unfortunately, however, trials using secretase inhibitors have been prematurely terminated in

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Fig. 1. Inter- and intramolecular cross-linking of peptides induced by tissue transglutaminase (tTG) cross-linking activity. The main activity of tTG is to catalyze a calcium-dependent acyl transfer reaction between the ␥-carboxamide group of a polypeptide-bound glutamine and the ␧-amino group of a polypeptide bound lysine residue to form an ␧-(␥-glutamyl)lysine isopeptide bond, also known as a cross-link. This characteristic reaction of tTG results in a posttranslational modification through either the formation of an intermolecular cross-link between two polypeptide chains, or an intramolecular cross-link within a single peptide chain.

THE AMYLOID CASCADE: TARGET FOR THERAPEUTIC INTERVENTION The amyloid cascade hypothesis for AD combines histopathological and genetic information on AD and posits that the deposition of A␤ peptide in the brain parenchyma initiates a sequence of events, including the formation of NFTs, that eventually leads to AD dementia. In the last few years, however, it has become clear that the rate of A␤ accumulation and deposition as SPs has no linear relationship to the development of dementia or other forms of cognitive impairment, in both humans and AD mouse models [30, 31]. Moreover, evidence is mounting that soluble A␤ oligomers, ranging from dimers up to mid range-molecular weight oligomers (e.g., A␤*56), account for the neurotoxicity observed in AD [32, 33]. This notion is supported by findings of McLean and coworkers, who demonstrated the presence of ∼8 and ∼12 kDa soluble SDS-stable A␤ dimers and trimers in AD brain tissue [34]. Elevated levels of SDS-stable A␤ dimers are also observed in AD mouse models and A␤ dimers isolated from AD brain tissue are capable of impairing long-term potentiation [21, 35, 36]. Overall, it is becoming evident that small A␤ oligomers are not only the likely neuro-

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TISSUE TRANSGLUTAMINASE Structure and function of tTG The secondary structure of tTG is composed of four domains (Fig. 2), the domains 1, 3, and 4 are folded in ␤-structures and domain 2 presents a ␣-helical structure [37]. The 13 tryptophan residues of the protein are all located in domains 1 and 2. The structural information concerning tTG and the domain-specific intrinsic spectroscopic probes are useful in studies of protein unfolding by chemical and thermal denaturation [38]. The transamidating activity of the enzyme is located in domain 2 and is regulated by the catalytic site in which Cys277 , His335 and Asp358 play an essential role (Fig. 2). Especially the highly reactive Cys277 in the catalytic core is of importance as it forms thioesters with peptidylglutamine moieties of the protein substrates. For instance, the in vivo toxicity of acrylamide toward the central nervous system is probably caused by the reaction of tTG with acrylamide, which results in inactivation of the enzyme [39]. Therefore, the high reactivity of active-site Cys277 has been used to develop irreversible inhibitors of the enzyme, as discussed later. Upon calcium binding, a conformational change in the protein is induced, creating an open access to the active site, and thus inducing the transamidating activity. The calcium-induced transamidating activity is counteracted by binding of guanosine-5′ -triphosphate to the enzyme. Guanosine-5′ -triphosphate binds at Lys173 and is finally hydrolyzed in a process which also involves serine171 , leading to a reversible, guanosine5′ -triphosphatase-dependent regulatory mechanism. Although the guanosine-5′ -triphosphate pocket is located at a long distance from the Cys277 , the spatial location is very close [40]. Therefore, guanosine-5′ triphosphate-binding can be considered as an allosteric inhibition of the enzyme. Another potential regulatory effect of tTG activity might occur by the interaction of tTG with phospholipids and following nitrosylation of cysteine residues by nitric oxide donors. Binding of a

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relatively minor membrane phospholipid component, lysophosphatidylcholine, to tTG increases the sensitivity of the enzyme to calcium, so that tTG acquires appreciable activity at near physiological levels of calcium [41]. Thus, this interaction broadens the cellular conditions under which tTG may be active. The nitrosylation of the enzyme by nitric oxide releasing agents induces another regulatory effect of tTG [42]. Nitrosylation results in a marked inhibition of activity and an increased sensitivity to the inhibitory effects of guanosine-5′ -triphosphate. Different sets of cysteine residues are nitrated in the absence or presence of calcium, but this modification only takes place in the presence of calcium and is apparently relevant in regulating the transamidating activity. As discussed, tTG is activated by the binding of calcium. This binding induces the acylation of the active site cysteine residue (Cys277 ) by a proteinbound glutamine residue, resulting in the liberation of ammonia and the formation of a thioester intermediate between tTG and the glutamine bearing protein substrate. Accordingly, the thioester intermediate is attacked by a nucleophilic primary amine, either a small molecule amine such as putrescine or the ␧amino group of a protein-bound lysine residues [43]. This results in the formation of a relatively stable isopeptide bond. This reaction can induce a bridge, cross-link, between a lysine donor residue of one protein with an acceptor glutamine residue of another protein, creating a cross-link between two proteins. In contrast, if both a lysine donor and a glutamine acceptor are present within a protein, this cross-link induces an intramolecular bridge [15]. Despite the lack of a leader sequence, tTG is transported to the cell surface in a controlled manner [44, 45]. Nitric oxide appears to play a role herein, at least in several vascular cell types [46]. Interestingly, tTG interacts at the cell surface with low-density lipoprotein receptor-related protein 1, which is a requirement for its endocytosis [47]. As also A␤ is transported by low-density lipoprotein receptor-related protein 1 in cerebrovascular cells [48], a potential interaction between A␤ and tTG can therefore be speculated upon. Work from Zemskov et al. suggests that tTG is removed from the cell surface via endosomes [47]. This constitutive endocytosis of tTG from the cell surface depends on plasma membrane cholesterol, dynamin-2, and involves both clathrin-coated pits and lipid rafts. In the extracellular milieu, a high calcium environment, tTG interacts with a number of extracellular proteins, such as fibronectin [49, 50], collagen [51], laminin [52], vitronectin and fibrinogen [53, 54]. By cross-linking these

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toxic species that directly lead to neurodegeneration in AD and in AD models, but that these stable oligomers also form the molecular building blocks for fibrillar A␤ in vivo. Thus, as stable A␤ oligomers appear to be of key importance in the amyloid cascade, the mechanisms leading to their formation may offer novel and attractive drug targets in AD. It is therefore an attractive hypothesis that disease-specific post-translational modification of monomeric A␤ by tTG might underlie the formation of SDS-stable neurotoxic A␤ oligomers.

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Fig. 2. Structure of tissue transglutaminase (tTG). The secondary structure of tTG is composed of four domains, the domains 1, 3, and 4 are folded in ␤-structures and domain 2 presents an ␣-helical structure. The N-terminal ␤-sandwich strand contains the fibronectin-binding domain. Domain 2 contains the guanosine-5′ -triphosphate-binding region, Ser171 and Lys173 and the calcium-binding region composed of Ser449 , Glu451 and Glu452 . The transamidating activity of the enzyme is located in domain 2 and is regulated by the catalytic site in which Cys277 , His335 and Asp358 play an essential role. Upon calcium binding, a conformational change in the protein is induced, creating an open access to the active site, and thus inducing the transamidating activity. During activation of the protein, the interactions between domains 2, 3, and 4 breakdown, creating a possibility for calcium to bind at the main binding site located domain 2. In addition, the active site becomes accessible upon calcium binding. As a consequence of the calcium binding, the ␣-helix (H4) unfolds resulting in perturbing of the structure of neighboring loop 455-478, which connects domains 2 and 3, and also the spatial location of domains 3 and 4, which move from each other and from domain 2. Guanosine-5′ -triphosphate binds at Lys173 and is finally hydrolyzed in a process which also involves serine171 , leading to a reversible, Guanosine-5′ -triphosphatase-dependent regulatory mechanism.

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matrix proteins, tTG does not only increase the proteolytic, chemical and mechanical resistance of these proteins, but is also thought to facilitate cell adhesion and motility, although cross-linking is just one of the activities of the enzyme that plays a role in cell adhesion [55, 56]. In this manner, the cross-linking function of tTG has been implicated in the maintenance of tissue integrity following damage. In fact, subsequent to tissue damage, both tTG levels and activity increase, and the enzyme might even be released into the matrix to stabilize the matrix via cross-linking.

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tTG is abundantly expressed in the human brain and is present in neurons in several brain areas includ-

ing the amygdala, corpus callosum, cerebellum, and frontal cortex [57]. More recent work of our group demonstrated that tTG is also expressed in astrocytes and microglial cells in the white matter [58]. In addition, we detected tTG in brain capillaries and other parenchymal vessels. Apart from the presence of tTG itself, we also detected the presence of TG-catalyzed cross-links in glial cells of both white and grey matter, and weak immunoreactivity of the anti-cross-linking antibody in brain vessels and in corpora amylacea [58, 59]. In cell lines and cultured primary brain-derived cells, tTG expression is mainly observed in the cytosolic compartment, but also in cell membranes and extracellular fractions. In addition, in cultured neuroblastoma cells, tTG has also been detected in the

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TTG IN AD

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these data using postmortem brain tissue point toward a role for tTG in SPs formation and/or stabilization [58] (Fig. 3). Next to the compelling in vivo evidence that tTG is associated with SPs in AD, in vitro data provide direct proof that tTG is able to affect the A␤ aggregation cascade. In early studies, both wild-type A␤1-40 and A␤1-40 with the Dutch mutation (Glu22 to Gln) were found to be good substrates for tTG cross-linking [74]. Moreover, tTG-catalyzed cross-linking resulted in the formation of A␤ oligomers [74] (Figs. 3 and 4). Ho and coworkers demonstrated that the A␤PP is a substrate for tTG-catalyzed cross-linking resulting in A␤PP dimers and multimers [75], and Schmid and colleagues showed that tTG induces intramolecular cross-links in A␤ [76]. Intriguingly, tTG-catalyzed intermolecular cross-linking of A␤ induces the formation of stable A␤ oligomers that are resistant towards A␤ degrading enzymes, in particular insulin degrading enzyme and neprilysin [77]. In addition, tTG-catalyzed crosslinking of A␤ lowers its oligomerization threshold for self aggregation, suggesting that tTG is capable of driving the aggregation process of A␤ at physiological A␤ levels (Fig. 3). Furthermore, these tTG-mediated A␤ oligomers and protofibrils are toxic in that they inhibit long term potentiation in the CA1 region of the hippocampus [77]. Earlier work on the effects of tTGcatalyzed cross-linking of A␤ had shown that when tTG activity is blocked in cultured neuroblastoma cells, A␤-induced cell death is reduced, whereas induction of tTG enhances A␤-driven neurotoxicity [78]. Moreover, A␤1-42 treatment of monocytes induces tTG expression in vitro [79]. Together, these data indicate that tTG is a likely candidate responsible for initiating the aggregation process of A␤ in AD brains by the formation of stable A␤ dimers, oligomers, and protofibrils (Fig. 4).

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tTG in SPs

There is strong evidence that tTG is linked to the pathology of AD. Both tTG levels and TG activity are elevated in the cortex of AD brains, compared to control patients [69]. Significantly elevated tTG levels have been reported in the cerebrospinal fluid of AD patients compared to controls [70], suggesting the potential to use tTG protein levels in the cerebrospinal fluid as a diagnostic marker for AD. Moreover, the level of ␧-(␥-glutamyl)lysine isopeptides was significantly elevated in the cerebrospinal fluid of AD patients [71]. In line with these data are the findings of Wang and colleagues, who described a correlation between accumulation of insoluble proteins containing isopeptide bonds in the gray matter with cognitive impairment in AD patients [72]. In addition to these biochemical data, immunohistochemical studies on postmortem tissue sections have shown that tTG enzyme is present in the A␤ core of SPs [73]. A more recent study of our own group confirmed these data and additionally showed colocalization of the tTG enzyme with both diffuse and classic SPs [58] (Fig. 3). The presence of tTG in diffuse SPs suggests an early involvement of tTG in SP formation, as diffuse SPs might be precursors of the classic SPs [1] (Fig. 3). More interestingly, we found the presence of TG-catalyzed cross-links in both diffuse and classic SPs [58], indicating that tTG is not only present but also catalytically active within these lesions. Together,

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nucleus [60]. Interestingly, we recently observed that tTG is associated with the endoplasmic reticulum (ER) in SH-SY5Y neuroblastoma cells, and is upregulated and activated at the ER under ER stress conditions induced by the Parkinson’s disease-mimetic 1-methyl4-phenylpyridinium [61]. These data obtained in cultures cells, were in line with observations in dopaminergic neurons in postmortem Parkinson’s disease brain [62]. tTG is suggested to play an important role in the development of the nervous system, since its expression level and activity changes significantly during development. For example, during the brain growth spurt, tTG activity levels increase dramatically, suggesting that tTG is involved in maturation of the brain [63]. In addition, tTG has been demonstrated to be essential for neuritic outgrowth, although its specific role in the formation of neurites in neurons remains to be elucidated [64–68].

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tTG in NFTs The first in vivo evidence that tTG is involved in NFT formation by cross-linking of tau into helical filaments was provided by Selkoe and coworkers in the early eighties [14, 80, 81]. Other groups subsequently found that the tau protein is indeed a substrate for tTG-catalyzed cross-linking, and that tTG-mediated cross-linking induces SDS-stable tau filament formation in a calcium-dependent manner [82–85] (Fig. 3). Both phosphorylated tau, which accumulates in NFTs, as well as non-phosphorylated tau are substrates for tTG [86]. Furthermore, tTG is able to polyaminate the tau protein, resulting in an increased resistance of

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Fig. 3. Tissue transglutaminase (tTG) and its catalyzed cross-linking in the formation Alzheimer’s disease (AD) pathological hallmarks. tTG-catalyzed cross-linking of amyloid-␤ (A␤) induces the formation of stable A␤ complexes in vitro, suggesting an early involvement of tTG cross-linking activity in AD pathology lesion formation. Studies on postmortem brain tissue of AD patients confirm this notion as the tTG enzyme and its cross-linking products are already found in diffuse senile plaques (SPs), the precursors of classic SPs [58]. These diffuse SPs, in contrast to classic SPs, do not contain ␤-pleated sheet A␤ fibrils, but already show the presence of tTG and its cross-linking products. In line with the observations in SP formation are the findings in cerebral amyloid angiopathy (CAA). In early stages of CAA, characterized by partial A␤ deposition in the cerebral vessel wall (CVW), elevated anti-tTG antibody immunoreactivity has been demonstrated compared to non-affected vessels [95]. However, in contrast to diffuse and classic SP, in which tTG and its cross-linking products colocalize with the deposited A␤, tTG (green) and its cross-links are present in halos surrounding the A␤ deposition (red) in late stage CAA [58, 95]. These halos are also characterized by the presence of extracellular matrix (ECM) [95], suggesting that in late stage CAA the deposited A␤ is surrounded by a cross-linked ECM network [16, 95]. Apart from the A␤ lesions in AD, tTG and its cross-linking activity are also observed during neurofibrillary tangles (NFT) formation. tTG is known to cross-link tau into anti-parallel dimers [88] that are suggested to precede filament formation. The presence of tTG-induced filaments and tTG cross-links in pretangles, a precursor stage of NFTs, suggests an early involvement in NFT formation. Finally, both tTG and its cross-links are also observed in mature NFTs in AD. Immunohistochemical staining using antibodies directed against either A␤, hyperphosphorylated tau, or tTG on postmortem AD brain tissue was performed as described in previous reports of our group [58, 62, 90, 95].

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tau to proteolytic degradation by calpain leading to higher levels of non-degradable tau within the neuron [87]. Of importance for the notion of an early involvement of tTG in NFTs formation is the finding of Murthy and colleagues, who demonstrated that tTG cross-links tau into an “anti-parallel dimer” that might act as a seed for further tau aggregation [88] (Fig. 3). Apart from these in vitro findings, both

we and others have observed tTG immunoreactivity and tTG-catalyzed cross-links in NFTs in AD brains [58, 82, 89–91] (Fig. 3). Interestingly, these intraneuronal tTG-catalyzed cross-links were found to increase during aging in the brain, albeit to a lesser extent as compared to AD brains [91, 92]. Purification of the helical filaments of AD brain tissue showed that the tau filaments contained TG-catalyzed cross-links

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[83, 93]. Interestingly, cross-linked tau filaments are found before NFTs are detected, indeed pointing toward an early role of tTG-catalyzed cross-linking of tau in the formation of NFTs [83, 91] (Fig. 3). Although cellular data on the role of tTG-mediated cross-linking is lacking, a transgenic mouse model of tau pathology, the P301L transgenic mouse, showed that the accumulating tau filaments are positive for TG-catalyzed cross-links and that the level of these crosslinks is significantly elevated compared to control mice [94].

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tTG in CAA and other cerebrovascular-related changes in AD The first evidence that tTG is present in CAA was provided by us in 2009, showing that both tTG and TG-catalyzed cross-links were present in halos surrounding the deposited A␤ in CAA-affected vessels [58] (Fig. 3). Surprisingly, in contrast to SPs, no actual spatial colocalization was found between the deposited A␤ and both tTG and TG-catalyzed crosslinks. However, both tTG and TG-catalyzed cross-links were detected in the endothelial cells at the luminal side and in perivascular cells at the abluminal side of the deposited A␤ [58] (Fig. 3). Following up on this study, we set out to further investigate the association of tTG and its activity with CAA, and found that in an early phase of CAA formation, elevated levels of

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Fig. 4. Intermolecular tissue transglutaminase (tTG) cross-links initiate the protein aggregation cascade. The aggregation cascade of amyloid-␤ (A␤) starts with an initiation process that induces the formation of dimers, followed by the formation of oligomers, protofibrils, and eventually mature fibrils. tTG is capable of inducing intermolecular cross-links between A␤ peptides. For the formation of a tTG-catalyzed intermolecular cross-link between two A␤ peptides the glutamine at position 15 (Q15 ) of one A␤ peptide and the lysine at position 16 (K16 ) of another A␤ peptide are of key importance. This intermolecular cross-link generates stable A␤ dimers that initiate the A␤ cascade [76, 77]. In addition, tTG-catalyzed cross-linking might also act as a driving force to accelerate further aggregation from dimer into oligomers and protofibrils [9]. Altough tTG and its cross-links are also detected in the pathological lesions containing mature ␤-pleated sheet fibrils, so far, data demonstrating a role for tTG-catalyzed cross-linking in the formation of mature A␤ fibrils formation is lacking.

tTG immunoreactivity do colocalize with the deposited A␤ in CAA [95] (Fig. 3). These findings are in line with the observations made in diffuse SPs, and suggest that tTG is likely to play an early role in both SP and CAA formation. In addition, in CAA, tTG and its cross-linking products colocalize with the extracellular matrix (ECM) proteins and tTG-substrates laminin and fibronectin [95], pointing towards tTG-catalyzed modification of the ECM in CAA (Fig. 3). Although the above described data support the idea that tTG activity might drive AD pathology, the presence tTG and/or its activity with these lesions might also be a consequence of lesion formation and associated factors that induce tTG levels and/or activity, e.g., reactive oxygen species and transforming growth factor-beta [96]. In addition, evidence based merely on the use of a single antibody directed against the ␧(␥-glutamyl)lysine bond needs to be interpreted with caution as immunoblots incubated with these antibodies do not solely detect ␧-(␥-glutamyl)lysine bond [97]. However, together, both the in vitro and the human postmortem AD brain tissue data provide compelling evidence that tTG activity not only colocalizes with the pathological hallmarks of AD but also induces stable and toxic oligomers of A␤ and tau, which are both crucial in AD pathogenesis. Therefore, blockade of tTG-catalyzed cross-linking activity in AD patients using tTG inhibitors may offer a new therapeutic approach for AD.

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The use of both competitive amine inhibitors and reversible inhibitors as therapeutic agents is questionable, since the inhibitory status of tTG is strongly dependent upon the local concentration of these inhibitors, which is related to their stability and breakdown rate in vivo. In addition, inhibition of tTG by guanosine-5′ -triphosphate is limited to conditions of suboptimal activation by calcium ions [105] which involves modulation of calcium binding affinity, interference with conformational changes induced by calcium, local alterations in domain flexibility, and increased strength of interaction between domain 4 and domains 1 and 2. The third class of inhibitors, the irreversible inhibitors, appear more promising. Irreversible inhibitors act via blockade of enzyme activity by covalently modifying the catalytic site of the enzyme and thereby prevent substrate binding. This modification entails targeting of the active site cysteine using functional groups that form stable chemical bonds after reacting. A well-studied irreversible inhibitor is iodoacetamide, which acts as an inhibitor of tTG by inducing the tTG active site thiol to form a stable thioether bond with iodoacetamide [106, 107]. Structurally, iodoacetamide is the simplest irreversible inhibitor of tTG, and therefore might be expected to be useful in therapeutic settings. However, the small structure of iodoacetamide prevents it from having a strong interaction with the enzyme, and although it is highly reactive, iodoacetamide is fairly non-selective in its inhibitory action toward active site cysteines. Thus, being such a non-selective inhibitor, iodoacetamide is likely to interact with nucleophilic residues other than the active site cysteine within tTG, causing unwanted side effects and toxicity [107]. Another class of irreversible inhibitors are the 3halo-4,5-dihydroisoxazoles, whose structure is based on acivicin that alike iodoacetamide acts as an inhibitor of active site cysteines [108]. These compounds are structurally typified by a 3-bromo-4,5dihydroisoxazole warhead group bound to a natural or synthetic amino acid via a peptide bond typically followed by a hydrophobic, aromatic moiety, which increases binding specificity to the tTG active site [109, 110]. The asymmetric nature of the interaction between dihydroisoxazoles and the tTG active site was established after purification of the R and S enantiomers around the C-5 carbon in the dihydroisoxazole ring, demonstrating that only the S enantiomer is able to irreversibly inhibit the enzyme [110, 111]. Their inhibitory activities involve the displacement of the active site thiol and forming a stable iminothioether. Although

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Based upon their mechanisms of inhibition, currently available tTG inhibitors can be divided into three classes: competitive amine inhibitors, reversible inhibitors, and irreversible inhibitors, respectively. The first class are the competitive amine inhibitors that are the best characterized inhibitors of tTG, since they are widely accessible, stable, and nontoxic [98, 99]. The primary amine bound to an aliphatic unbranched carbon chain of around 4-5 saturated carbon atoms is the characteristic structure of this class of inhibitors, although shorter amines such as hydroxylamine and methylamine are also tTG substrates. Amine inhibitors function by competing with other natural amine substrates for tTG in the transamidation reaction. tTG is therefore still active, yet the isodipeptide cross-link is now formed between the natural glutamine substrate and the competitive amine inhibitor rather than between the natural glutamine substrate and natural amine substrates. Wellknown competitive amine inhibitors are putrescine, cystamine, spermidine, histamine, and cadaverine analogues like monodansylcadaverine [43]. Cystamine is probably the most extensively studied inhibitor of this type, although it should not be considered as a specific inhibitor for tTG when applied in biological systems, since cystamine has also been shown to inhibit the thiol-dependent protease caspase-3 and causes increased production of the anti-oxidant glutathione inside cells [100]. The second class of inhibitors is the reversible inhibitors of tTG, which prevent tTG activity by inhibiting substrate access to the active site without covalently modifying the enzyme. Both GTP and GDP are reversible inhibitors, but also guanosine-5′ -triphosphate analogues such as GTP␥S and ␤␥-methyleneguanosine 5′ -triphosphate demonstrate this reversible inhibitory effect on tTG [101]. As described earlier, guanosine-5′ -triphosphate binds tTG and prevents binding of calcium to its binding site on tTG in an allosteric fashion. The divalent metal ion Zn2+ is also capable of reversibly inhibiting tTG activity by competing with Ca2+ for its binding site in the protein [43, 102]. Recently, a new class of reversible inhibitors for tTG has been discovered. These inhibitors are characterized by having a thieno[2,3-d]pyrimidin-4-one acylhydrazide backbone [103, 104]. They exhibit slow-binding kinetics, and kinetic analysis suggests that they possibly compete with guanosine-5′ -triphosphate, since they share the same tTG-binding site.

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3-halo-4,5-dihydro-isoxazole reactive group, demonstrated to be a potent tTG inhibitor in vitro and in vivo [118] and was found to disrupt fibronectin assembly in the extracellular matrix of gliobastomas, which resulted in enhanced apoptosis of these tumors in vitro [125]. Similar observations were made in vivo using a murine orthotopic brain tumor model [125]. In addition, inhibition of tTG activity by KCC009 influenced the ability of dendritic cells to mature upon LPS stimulation [126]. The use of KCC009 as a therapeutic agent in humans is strengthened by the fact that it is well tolerated in pharmacologically effective doses, at least in rodents, and that it has a short serum half-life, indicating a fast distribution over organs and tissues [109]. Recently, in vivo administration of another irreversible site-directed tTG inhibitor ERW1041E in a murine pulmonary hypertension model resulted in a significant reduction in right ventricular systolic pressure [127]. CONCLUSIONS, CRITICAL NOTES, AND FUTURE PERSPECTIVES

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this type of inhibitors seemed promising, as they have good bioavailability and low toxicity, their low solubility in buffers at physiological pH caused difficulties in using them as therapeutic agents. Other irreversible inhibitors were designed using natural substrates of tTG as a backbone. For instance, the tTG substrate carbobenzyloxy-Lglutaminylglycine (Cbz-gln-gly) was used to produce a family of tTG inhibitors having different electrophilic functional groups by substituting the reactive moieties in the Gln position. Functional groups such as the chloroacetamides [112], maleimides [113], 1,2,4thiadiazoles [114, 115], epoxides and ␣,␤-unsaturated amides [106] were used for this purpose. Both the Cbz-gln(epoxide) and the Cbz-gln(␣,␤-unsaturated)gly were found to be the most potent inhibitors of tTG in these studies, albeit so far only in vitro. An alternative approach used the high affinity binding of gluten peptides to tTG [116]. The sequence of these gluten peptides served as a blueprint to design several peptidomimetic inhibitors [117]. The tTG target glutamine in these gluten peptides was replaced by, for instance, 6-diazo-5-oxo-norleucine (DON), which demonstrated a potent irreversible inhibitory effect. In fact, the DON containing peptide was found to be 5 orders of magnitude more potent than the acivicin analogue. More recently, our group confirmed the potency and efficacy of the DON-based inhibitors Boc-DONGln-Ile-Val-OMe and Z-DON-Val-Pro-Leu-OMe to inhibit tTG activity both in vitro and in a cellular assay [118]. Although information is still limited, several irreversible inhibitors of tTG have already demonstrated to be promising as therapeutic agents in human diseases. An effective class of inhibitors of FXIIIa, the 2-[(2-oxopropyl)thio]imidazolium derivatives, have been used as inhibitors of tTG in vivo [119]. In fact, the 2-[(2-oxopropyl)thio]imidazolium inhibitor L682777 prevented gluten peptide deamidation, which resulted in reduced T-cell activation in celiac sprue mouse models [120]. Although this group of compounds are fairly good inhibitors of TG2 [119], and are effective in numerous biological settings [117, 120, 121], including mouse models of cardiovascular disease [122–124], the potential side-effects caused by inhibition of the blood coagulating factor XIIIa, makes the 2-[(2oxopropyl)thio]imidazolium inhibitors inappropriate for use in humans. Newer classes of peptidomimetic selective and irreversible tTG inhibitors have begun to be evaluated. Interestingly, the selective and irreversible tTG-inhibitor KCC009, which contains a

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From a pharmacological perspective, testing of tTG inhibitors in animal models of neurodegenerative diseases is a promising approach. For instance, the tTG inhibitor cystamine is known to delay the onset of neurological symptoms associated with Huntington’s disease when applied in the R6/2 Huntington’s disease mouse model. Moreover, the tTG-inhibitors cystamine, monodansylcadaverine, L-682777, KCC009, and recently ERW1041E [127], have been successfully used to inhibit tTG activity in other human disease models [128]. These data suggest that effective inhibition of tTG activity in vivo is feasible. However, studies on the effects of specific tTG inhibitors in dedicated models of AD are still lacking but will be indispensable for moving onwards in evaluating the therapeutic potential of tTG inhibition. Until recently, the insoluble mature fibrils of A␤ were considered to be the toxic species in the aggregation cascade resulting in neurodegeneration. However, smaller soluble oligomers are now thought to be the most neurotoxic species, as their presence in the brain is directly linked to neurotoxicity and cognitive decline [36, 129]. Since tTG-catalyzed cross-linking predominantly results in the formation of soluble A␤ multimers, and not the formation of insoluble mature ␤-pleated sheet fibrils, tTG inhibition might indeed prove to be a particularly attractive therapeutic target (Fig. 4). Within this context it is of interest that, according to the A␤ cascade, the accumulation of toxic

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This work was supported by a grant from The Brain Foundation of the Netherlands (number F2010(1)-06

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A␤ species precedes the formation of hyperphosphorylated tau resulting in NFTs. One of the proposed actions of toxic intermediates of A␤ on neurons is that they stimulate tau hyperphosphorylation and aggregation, and increase intracellular calcium levels [130]. As phosphorylation of tau alone is not sufficient to cause NFTs, it is an appealing hypothesis that the A␤induced dysregulation of calcium homeostasis results in an intracellular increase in tTG activity, ultimately resulting in production of stable tau aggregates and filaments [82]. Clearly, besides elucidation of tTG’s involvement in the A␤ cascade, further studies are also needed to determine the contribution of tTG activity to NFT formation, and investigate whether inhibition of tTG-catalzyed cross-linking of tau could prevent tau aggregation in AD. Since tTG activity is widely spread throughout the human body and is involved in many biological processes, tTG inhibition might be expected to result in severe side-effects. However, tTG knockout mice do not appear lethal and show no major pathological features [131, 132]. Furthermore, the above-described amine and reversible inhibitors demonstrate low toxicity. Thus, contrary to expectations, specific inhibition of tTG does not appear to cause dramatic side-effects in vivo. Nevertheless, if tTG inhibitors are considered for use in AD, they will have to be administered in a chronic fashion and studies on the long-term use of these inhibitors in animal or humans have not been carried out thus far. Within this context, another important consideration for the use of tTG inhibitors in AD is their ability to cross the blood-brain barrier. Currently, no information regarding their brain penetration is available. Although in theory it is likely that small amine-based inhibitors are capable of crossing the blood-brain barrier, other properties for good bloodbrain barrier transport, i.e., the lack of charged groups and lipophilicty, have not been taken into account in current tTG inhibitor drug design. However, encouraging for future drug design of specific and selective tTG inhibitors able to cross the BBB is the extensive knowledge already present regarding the structure of tTG, as described above. This knowledge will guide the development of optimized tTG inhibitors which will enable investigation of the full therapeutic potential of tTG blockade in the brain, first in AD models and eventually in AD patients.

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