Impaired mitochondrial energy metabolism in Alzheimer's disease: Impact on pathogenesis via disturbed epigenetic regulation of chromatin landscape.

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Contents lists available at ScienceDirect

Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio 1 2 3 4 5 6 7 8 9 10 11

Impaired mitochondrial energy metabolism in Alzheimer’s disease: Impact on pathogenesis via disturbed epigenetic regulation of chromatin landscape Salminen a,*, Annakaisa Haapasalo a,b, Anu Kauppinen c,d, Kai Kaarniranta c,d, Hilkka Soininen a,b, Mikko Hiltunen a,b,e

Q1 Antero

a

Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Department of Neurology, Kuopio University Hospital, P.O. Box 100, FI-70029 KYS, Finland c Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland d Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029 KYS, Finland e Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 31 October 2014 Received in revised form 5 May 2015 Accepted 11 May 2015 Available online xxx

The amyloid cascade hypothesis for the pathogenesis of Alzheimer’s disease (AD) was proposed over twenty years ago. However, the mechanisms of neurodegeneration and synaptic loss have remained elusive delaying the effective drug discovery. Recent studies have revealed that amyloid-b peptides as well as phosphorylated and fragmented tau proteins accumulate within mitochondria. This process triggers mitochondrial fission (fragmentation) and disturbs Krebs cycle function e.g. by inhibiting the activity of 2-oxoglutarate dehydrogenase. Oxidative stress, hypoxia and calcium imbalance also disrupt the function of Krebs cycle in AD brains. Recent studies on epigenetic regulation have revealed that Krebs cycle intermediates control DNA and histone methylation as well as histone acetylation and thus they have fundamental roles in gene expression. DNA demethylases (TET1-3) and histone lysine demethylases (KDM2-7) are included in the family of 2-oxoglutarate-dependent oxygenases (2-OGDO). Interestingly, 2-oxoglutarate is the obligatory substrate of 2-OGDO enzymes, whereas succinate and fumarate are the inhibitors of these enzymes. Moreover, citrate can stimulate histone acetylation via acetyl-CoA production. Epigenetic studies have revealed that AD is associated with changes in DNA methylation and histone acetylation patterns. However, the epigenetic results of different studies are inconsistent but one possibility is that they represent both coordinated adaptive responses and uncontrolled stochastic changes, which provoke pathogenesis in affected neurons. Here, we will review the changes observed in mitochondrial dynamics and Krebs cycle function associated with AD, and then clarify the mechanisms through which mitochondrial metabolites can control the epigenetic landscape of chromatin and induce pathological changes in AD. ß 2015 Published by Elsevier Ltd.

Keywords: Epigenetics Histone acetylation Histone methylation Krebs cycle Mitochondrial dynamics Retrograde signaling

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Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mitochondrial changes in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Changes in mitochondrial dynamics . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Accumulation of APP and amyloid-b peptides into mitochondria . 2.2. Toxic effect of tau proteins on mitochondrial function. . . . . . . . . . 2.3.

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Abbreviations: ACL, ATP-citrate lyase; AD, Alzheimer’s disease; APP, amyloid-b precursor protein; BACE, b-site APP-cleaving enzyme; C/EBP, CCAAT-enhancer binding protein; DNMT, DNA methyltransferase; Drp, dynamin-related protein; ER, endoplasmic reticulum; FH, fumarate hydratase; GABA, g-aminobutyric acid; HAT, histone acetyltransferase; HDAC, histone deacetylase; HIF, hypoxia-inducible factor; KDM, histone lysine demethylase; LSD, lysine-specific demethylase; Mfn, mitofusin; 2-OGDH, 2oxoglutarate dehydrogenase; 2-OGDO, 2-oxoglutarate-dependent oxygenase; OXPHOS, oxidative phosphorylation; PHD, prolyl 4-hydroxylase; ROS, reactive oxygen species; SDH, succinate dehydrogenase; SIRT, silent information regulator; TET, Ten-Eleven Translocation. * Corresponding author. E-mail address: antero.salminen@uef.fi (A. Salminen). http://dx.doi.org/10.1016/j.pneurobio.2015.05.001 0301-0082/ß 2015 Published by Elsevier Ltd.

Please cite this article in press as: Salminen, A., et al., Impaired mitochondrial energy metabolism in Alzheimer’s disease: Impact on pathogenesis via disturbed epigenetic regulation of chromatin landscape. Prog. Neurobiol. (2015), http://dx.doi.org/10.1016/ j.pneurobio.2015.05.001

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Mitochondrial energy metabolism disturbances in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impaired Krebs cycle function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Decline in oxidative phosphorylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Anaplerosis and cataplerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Energy metabolites control the epigenetic landscape of chromatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-Oxoglutarate-dependent oxygenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Krebs cycle metabolites regulate DNA and histone methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Acetyl-CoA-related pathways regulate histone acetylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. 4.4. NAD+ and FAD+-dependent regulation of the epigenetic landscape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigenetic changes in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Potential role of impaired mitochondrial energy metabolism in the epigenetic regulation of AD pathogenesis Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

16 Q2 Alzheimer’s disease (AD) is a progressive neurodegenerative 17 disorder involving a gradual decline in cognitive capacities, 18 eventually leading to dementia. The deposition of amyloid-b19 containing extracellular plaques and the intracellular accumula20 tion of hyperphosphorylated tau-protein into neurofibrillary 21 tangles are the two histopathological hallmarks of AD (Selkoe, 22 2001). Despite extensive research, the pathogenesis of AD is still 23 not well understood and there are only symptomatic treatments 24 for AD. In 1991, Hardy and Allsop formulated the amyloid cascade 25 hypothesis, postulating that the processing of amyloid-b precursor 26 protein (APP) into toxic amyloid-b peptides would play a key role 27 in the pathogenesis of AD leading to the deposition of neuritic 28 plaques. This hypothesis has represented the main principle in the 29 field of AD research. In 2004, Swerdlow and Khan presented the 30 mitochondrial cascade hypothesis which placed greater emphasis 31 on the crucial role of mitochondrial dysfunction in late-onset AD. 32 They underlined the role of oxidative stress and the decline in the 33 efficiency of oxidative phosphorylation as a mechanism involved 34 on the route to amyloid-b-induced pathology in AD. Recently, they 35 noted that mitochondrial dysfunction appeared to be an upstream 36 regulator of amyloid cascade, e.g. affecting APP processing 37 (Swerdlow et al., 2014). Interestingly, there is mounting evidence

Fig. 1. An overview of the connections between the major Krebs cycle metabolites to neurotransmitter synthesis and the epigenetic regulation of chromatin landscape. The citrate/acetyl-CoA pathway controls acetylcholine and fatty acid synthesis as well as histone acetylation. 2-Oxoglutarate regulates glutamate synthesis and triggers the GABA shunt. Moreover, 2-oxoglutarate activates DNA and histone demethylases, whereas succinate and fumarate inhibit these enzymes and increase DNA and histone methylation. The reactions between 2-oxoglutarate, glutamate and non-essential amino acids can be reversible. ACL, ATP-citrate lyase; FA, fatty acid; NEA, nonessential amino acid; 2-OGDH, 2-oxoglutarate dehydrogenase.

that amyloid-b can accumulate within intracellular compartments, especially in the mitochondria, and affect mitochondrial dynamics and disturb mitochondrial energy metabolism (LaFerla et al., 2007; Reddy, 2009; Chen and Yan, 2010; Pagani and Eckert, 2011; DuBoff et al., 2013). There are emerging studies demonstrating that mitochondrial energy metabolism regulates the epigenetic landscape of chromatin via the intermediates of the Krebs cycle, i.e. 2-oxoglutarate, citrate, succinate and fumarate (Kaelin and McKnight, 2013; Benit et al., 2014; Salminen et al., 2014a,b) (Fig. 1). The key enzymes removing the methyl groups from DNA and histones are members of a family of 2-oxoglutarate-dependent oxygenases (2-OGDO), i.e. Ten-Eleven Translocation 1-3 (TET1-3) which undertake DNA demethylation whereas the Jumonji C domain containing histone lysine demethylases 2-7 (KDM2-7) are the main demethylating enzymes of histones (Section 4.2). 2-Oxoglutarate is a mandatory compound for the activation of 2-OGDO enzymes, whereas two other Krebs cycle intermediates, succinate and fumarate, correspondingly are potent inhibitors of these enzymes. This indicates that Krebs cycle intermediates are involved in retrograde epigenetic signaling from the mitochondria to the nucleus. This may reflect the endosymbiont origin of eukaryotic cells, when aerobic bacteria invaded anaerobic archael prokaryotic cells and later they were transformed to mitochondria (Gray et al., 1999; Davidov and Jurkevitch, 2009). There is mounting evidence that in AD there are changes appearing in the epigenetic landscape of chromatin, which could affect the pathogenesis, particularly induce disturbances in late-onset AD (Section 5). Given that amyloid-b can impair the mitochondrial energy metabolism, it seems that Krebs cycle intermediates can disturb not only neurotransmitter synthesis (Section 3.3) but also induce the stochastic disruption of gene expression and thus trigger neuronal degeneration (Fig. 2). We will review how changes in mitochondrial dynamics and energy metabolism can be linked to the neuronal disturbances encountered in AD and subsequently examine the emerging evidence that energy metabolism can shape the epigenetic landscape of chromatin and thus influence gene expression. Finally, we will discuss the potential role of epigenetic disturbances induced by impaired energy metabolism in the pathogenesis of AD.

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2. Mitochondrial changes in AD

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2.1. Changes in mitochondrial dynamics

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Mitochondria are dynamic cellular organelles; their morphology is regulated by several large GTPases (Palmer et al., 2011; Chan, 2012; Otera et al., 2013; Dhingra and Kirshenbaum, 2014). Mitofusin 1 and 2 (Mfn1 and Mfn2) along with Optical atrophy 1 (Opa1) control the fusion (elongation) of mitochondria, whereas

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Fig. 2. A schematic presentation on the epigenetic changes induced by the mitochondrial disturbances induced by increased accumulation of amyloid-b/APP and fragmented (NH2-TAU) and phosphorylated tau (TAU-P) proteins inside of mitochondria. Impaired Krebs cycle function in conjunction with increased mitochondrial fragmentation (fission) control the availability of metabolites, which in turn affects the chromatin landscape and thus disturbs gene expression. Hypoxia, ROS generation and Ca2+ imbalance are common factors linked to AD pathology, which can control the epigenetic regulation at different levels. Alterations in gene expression induce distinct epigenetic feedback responses, either adaptive or detrimental, influencing the maintenance of neuronal homeostasis.

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the Dynamin-related protein 1 (Drp1), Fission 1 protein (Fis1) and Mitochondrial fission factor (Mff) are the major proteins involved in the fission (division, fragmentation) of mitochondria (Fig. 2). Changes in the size of mitochondria are associated with many physiological and pathological processes, e.g. mitochondrial energy metabolism, quality control and cellular distribution as well as mitophagy (autophagy of mitochondria) and apoptotic cell death. The function of the mitochondrial network is controlled not only by changes in the expression levels of fusion/fission components but via their post-translational processing, e.g. phosphorylation, sumoylation, ubiquitination, and proteolytic cleavage. Drp1 is normally a cytoplasmic protein but its activation triggers its translocation to the mitochondrial outer membranes, where it targets several fission receptors, i.e. Fis1 and Mff proteins (Palmer et al., 2011; Reddy et al., 2011; Oettinghaus et al., 2012; Cho et al., 2013; Ishihara et al., 2013). Protein kinase Cd, induced by oxidative stress, and protein phosphatase calcineurin, activated by Ca2+ overload, are the main activators of Drp1 and thus can evoke mitochondrial fragmentation. In contrast, cyclic AMP-dependent protein kinase A and AMP-dependent kinase are the major inhibitors of Drp1 and subsequently they stimulate mitochondrial biogenesis and elongation. A detailed examination of the fusion and fission mechanisms is beyond the scope of this review but they have been described in detail in the articles cited above. There is substantial evidence indicating that mitochondrial dynamics become impaired in many neurodegenerative diseases, i.e. mitochondrial fission (fragmentation) seems to be increased in a Drp1-dependent manner (Reddy et al., 2011; Oettinghaus et al., 2012). There is an abundant literature indicating that the key elements of mitochondrial dynamics are altered in AD and moreover, many lines of evidence even imply that this might be a cause of the lateonset pathology rather than simply being a consequence. Ultrastructural studies, although technically problematic when

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conducted from post-mortem samples, have indicated that the number of mitochondria and the volume of mitochondrial space are reduced in affected neurons in AD (Hirai et al., 2001; Baloyannis, 2006). Wang et al. (2008a) demonstrated that the overexpression of wild-type APP and APPswe mutations in M17 neurons displayed shorter and swollen mitochondria, which were especially accumulated around the perinuclear area. A disturbance in mitochondrial distribution has been observed in several AD studies, i.e. there is a clear reduction of mitochondrial numbers in the axonal and dendritic space, whereas mitochondria are gathering in the neuronal soma (Iijima-Ando et al., 2009; Wang et al., 2009; Calkins et al., 2011). Calkins et al. (2011) revealed that mitochondria were fragmented and accumulated within the soma compartment in cultured primary neurons from transgenic AD mice. Moreover, the neurites displayed a decrease in the numbers and also in the size of the mitochondria present in transgenic AD mice. They also demonstrated that the speed of the anterograde transport of mitochondria in axonal projections was significantly lower in transgenic AD neurons than in their wild-type counterparts. It is known well that axonal transport is impaired in AD brain (Stokin and Goldstein, 2006; Kanaan et al., 2013). Li et al. (2004) demonstrated that the deficiency of fission factors, Drp1 and Opa1, reduced the mitochondrial contents in dendrites, and this caused a loss of synapses and a disappearance of dendritic spines in cultured rat hippocampal neurons. There are many indications that fission factors regulate mitochondrial distribution in neurons and thus synaptic degeneration in neurodegenerative diseases (Reddy et al., 2011). Manczak et al. (2011) reported that the expression of mitochondrial fission genes, Drp1 and Fis1, was increased at both the mRNA and protein levels in the frontal cortex of AD patients, whereas the expression levels of fusion genes, Mfn1, Mfn2, and Opa1, were significantly reduced (Fig. 2). Moreover, Wang et al. (2009) demonstrated that the protein level of Drp1 was increased in the mitochondrial fraction of AD brain, especially that of phosphorylated Drp1. They also revealed that the modulation of the expression of fission/fusion genes controlled mitochondrial distribution in differentiated primary neurons in culture, mimicking the changes observed in AD brain. These observations indicated that the fission rate of mitochondria was increased in AD, also leading to changes in the mitochondrial distribution in the affected neurons of AD brain. On the other hand, loss of fusion proteins in AD affects mitochondrial quality control (Alavi and Fuhrmann, 2013) and this can result in endoplasmic stress (ER), especially in the case of Mfn2 deficiency (Ngoh et al., 2012). Neuronal ER stress is increased in AD and this stress is believed to enhance inflammatory responses (Salminen et al., 2009a). Currently, the role of fission/fusion proteins in the pathogenesis of AD has remained elusive, although changes in mitochondrial dynamics are known to affect energy metabolism (Westermann, 2012; Liesa and Shirihai, 2013) and mitophagy (Twig and Shirihai, 2011), both phenomena which are disturbed in AD. Many factors, known to be involved in AD pathology, can control mitochondrial fission, e.g. disturbances in amyloid-b and reactive oxygen species (ROS) production and calcium homeostasis (Hom et al., 2010; Oettinghaus et al., 2012; Reddy, 2014).

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2.2. Accumulation of APP and amyloid-b peptides into mitochondria

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The deposition of amyloid-b peptides into senile plaques outside of neurons is a typical hallmark of AD. However, there is growing evidence indicating that both APP and amyloid-b peptides can also be translocated into mitochondria, where they interact with distinct mitochondrial proteins, disturbing mitochondrial function (Anandatheerthavarada and Devi, 2007; Reddy, 2009; Chen and Yan, 2010; Muirhead et al., 2010) (Fig. 2).

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Anandatheerthavarada et al. (2003) demonstrated that the APP695 isoform could be imported into mitochondria using its NH2terminal amino acids as a signal sequence. However, APP was incompletely translocated through mitochondrial membranes since it could be blocked by mitochondrial translocases. The transmembrane-arrested APP impaired mitochondrial energy metabolism in the neurons of APP-overexpressing transgenic AD mice, e.g. the accumulation of APP into mitochondria was associated with a 20–40% decrease in the activity of cytochrome c oxidase, a commonly observed alteration in AD brain (Section 3.2). Hansson Petersen et al. (2008) revealed that toxic amyloidb1-42 peptides could be transported into mitochondria via the translocase machinery of outer membrane (TOM). Immuno electron microscopy revealed that amyloid-b peptides were located within mitochondrial christae. They also reported that human neuroblastoma cells were able to internalize the extracellulary applied amyloid-b peptides and transport them into mitochondria. There are also studies indicating that amyloid-b peptides can be cleaved by the mitochondrial presequence protease (PreP), which alleviates the toxic effects of amyloid-b on mitochondrial energy metabolism (Pinho et al., 2014). The cellular aspects of mitochondrial uptake of APP and amyloid-b peptides still need to be more thoroughly clarified. Amyloid-b peptides can interact with several mitochondrial proteins and disturb energy production e.g. by increasing oxidative stress and impairing energy metabolic pathways (Atamna and Frey, 2007; Chen and Yan, 2010; Pagani and Eckert, 2011). Lustbader et al. (2004) demonstrated that amyloid-b peptides interacted with the enzyme called amyloid-b-binding alcohol dehydrogenase (ABAD) in the mitochondria of both AD patients and transgenic AD mice. They also revealed that the binding of amyloid-b to ABAD prevented the binding of NAD+ to ABAD, which stimulated ROS generation within the mitochondria. Later studies have identified that the ABAD enzyme is 17b-hydroxysteroid dehydrogenase type 10 (17b-HSD10) having only marginal alcohol dehydrogenase activity (Yang et al., 2014). There are observations that the level of 17b-HSD10 is robustly increased in AD patients as well as in transgenic AD mice (Kristofikova et al., 2009; Yao et al., 2011a; Yang et al., 2014). The interaction between amyloid-b and 17b-HSD10 in mitochondria was found to exacerbate the amyloidb-induced mitochondrial dysfunction and to enhance the severity of neurodegeneration. Yao et al. (2011a) reported that the prevention of the interaction between amyloid-b and 17bHSD10 with a decoy peptide could reduce oxidative stress and increase mitochondrial respiration in transgenic AD mice, also improving their spatial learning and memory. Moreover, deficiencies in the expression and activities of 17b-HSD10 enzyme can disturb mitochondrial function and provoke neurodegeneration, although the exact mechanism is still unknown (Yang et al., 2011). Manczak et al. (2011) demonstrated that amyloid-b peptides interacted with fission protein Drp1 in the mitochondria of AD patients and the co-localization appeared to be increased with the progression of disease. Neurons from transgenic AD mice also displayed a similar co-localization of amyloid-b and Drp1, which was also enhanced with increased neuronal degeneration. These observations clearly indicate that the mitochondrial import of APP and amyloid-b peptides can stimulate mitochondrial fragmentation and disturbs energy metabolism. Extracellular amyloid-b oligomers and fibrils can activate several pattern recognition receptors and control neuronal functions via distinct signaling pathways (Salminen et al., 2009b). For instance, there are reports that amyloid-b oligomers can target receptors for advanced glycation end products (RAGE) and potentiate amyloid-b-induced neuronal perturbation in transgenic AD mice (Arancio et al., 2004). Takuma et al. (2009) observed that RAGE receptors increased the uptake of amyloid-b

into neurons, appearing in both cytosol and mitochondria, and consequently reduced mitochondrial respiration. AD is also associated with inflammatory milieu in the brain containing increased levels of many cytokines and chemokines. Neuronal cells have receptors for many cytokines and chemokines, which can mediate either neurodegenerative or neuroprotective effects. It is known that mitochondrial dysfunction can trigger inflammatory responses in age-related diseases, e.g. via the activation of inflammasomes (Salminen et al., 2012). Changes in mitochondrial dynamics can also regulate the expression of pro-inflammatory cytokines in microglial cells (Park et al., 2013a). On the other hand, cytokines can control mitochondrial homeostasis, e.g. in adipocytes (Hahn et al., 2014) and neurons (Stommel et al., 2007). Stommel et al. (2007) observed that the treatment of rat motoneurons with TNF-a induced a redistribution of mitochondria to the soma part of the nerve, as observed in AD neurons (Section 2.1). These observations indicate that there seems to be a reciprocal crosstalk between mitochondrial metabolism and inflammation in AD brain.

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2.3. Toxic effect of tau proteins on mitochondrial function

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Recently it has been demonstrated that the tau protein, i.e. phosphorylated tau and the truncated forms of tau protein, can also control mitochondrial dynamics and toxicity (DuBoff et al., 2013; Go¨tz et al., 2013) (Fig. 2). Manczak and Reddy (2012a) reported that the hyperphosphorylated tau protein interacted with Drp1 in the neurons of AD patients and transgenic AD mice. They proposed that this interaction could enhance the enzymatic activity of Drp1, as observed with truncated tau proteins (see below), and consequently provoke mitochondrial fragmentation. Recently, Manczak and Reddy (2012b) observed that phosphorylated tau protein, as well as amyloid-b peptides, interacted with the mitochondrial voltage-dependent anion channel 1 (VDAC1), a metabolite diffusion channel located in the mitochondrial outer membrane, both in the brains of AD patients and transgenic AD mice. This effect most likely disturbed the function of mitochondrial permeability transition pore complexes. DuBoff et al. (2012) demonstrated that transgenic mice with overexpression of human tau protein carrying the P301L mutation displayed an elongated morphology in the mitochondria in their hippocampal pyramidal neurons. The P301L mutation is associated with a human tauopathy called frontotemporal dementia (FTDP-17). Moreover, they studied the mechanism of mitochondrial elongation in Drosophila. They revealed that the depletion of MARF, an Mfn homolog, normalized mitochondrial morphology and induced a significant rescue from neurotoxicity in the neurons overexpressing Drp1 protein. They observed that the expression of mutated tau prevented the transfer of cytoplasmic Drp1 protein into mitochondria and thus enhanced the fusion of mitochondria. The Drp1 protein was associated with F-actin, especially with actin stress fibers. It seems that the dysfunction of cytoskeletal actin and myosin proteins can control the Drp1 localization and thus induce neurodegeneration via impaired mitochondrial energy metabolism. It is known that the presence of amyloid-b can provoke the formation of actin stress fibers in neurons (Song et al., 2002). This is in line with the observations that amyloid-b peptide and tau protein induced a synergistic dysfunction in mitochondrial oxidative phosphorylation which subsequently provoked neurodegeneration (Rhein et al., 2009; Eckert et al., 2011). In conjunction with the hyperphosphorylation of tau, tau protein can also be cleaved by caspases enhancing neurofibrillary tangle formation during the early phase of AD (Gamblin et al., 2003; Rissman et al., 2004; Binder et al., 2005). Quintanilla et al. (2012) reported that the cleavage of tau protein at Asp421, an early event in AD (Rissman et al., 2004), impaired mitochondrial

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dynamics in cultured cortical neurons. The truncated tau significantly increased the fragmentation of neuronal mitochondria and decreased their axonal transport, especially in amyloid-b-treated neurons. In fact, amyloid-b and truncated tau enhanced oxidative stress in a synergistic manner. There is another caspase-truncated tau fragment of 20–22 kDa, called NH2 human tau (NH2hTau), which can affect mitochondrial dynamics and disturb the quality control of neuronal mitochondria (Amadoro et al., 2014). Amadoro et al. (2014) demonstrated that the expression of NH2hTau in cultured rat hippocampal neurons induced mitochondrial fission and their mislocalization to the soma part of the nerve, as observed in the amyloid-b-treated neurons (Section 2.2). Disturbances in mitochondrial dynamics were closely linked to the synaptic pathology in cultured neurons. Amadoro et al. (2012) observed that the NH2hTau fragment interacted with amyloid-b and mitochondrial adenine nucleotide translocator-1 (ANT-1), inhibiting ADP/ATP exchange. They also reported that the NH2hTau fragment was present in affected neurons in the AD brains, where it colocalized with ANT-1 to clustered mitochondria in the soma part as well as in synaptic mitochondria. Moreover, the expression of NH2hTau peptide elevated ROS production and decreased the activity of cytochrome c oxidase, as observed in AD brains (Section 3.2). Bobba et al. (2013a) demonstrated that the ROS production induced by amyloid-b could trigger the interaction with NH2hTau and ANT-1. In support of this observation, it was also reported that NH2hTau promoted the amyloid-b-induced changes in mitochondrial dynamics (Amadoro et al., 2012; Bobba et al., 2013b). It seems that this tau pathology can aggravate the disturbances induced by amyloid-b in mitochondrial dynamics, enhancing the impairment of energy metabolism during the early phase of AD.

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3. Mitochondrial energy metabolism disturbances in AD

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There are numerous studies indicating that disturbances in mitochondrial dynamics are closely associated with a disruption of mitochondrial bioenergetic status (Westermann, 2012; Van Laar and Berman, 2013). On the other hand, defects in mitochondrial respiration can trigger the fission of mitochondria, as well as mitochondrial damage can induce the Drp1-dependent mitochondrial fragmentation and depolarization which in many cases enhance neuronal apoptosis. In contrast, the fusion of depolarized mitochondria with their more polarized counterparts can prevent their degradation via mitophagy. These examples indicate that mitochondrial dynamics and energy metabolism are engaged in an intimate relationship in the maintenance of mitochondrial homeostasis and energetic state of cells. As described in Section 2, there are clear changes in mitochondrial dynamics in AD which are associated with significant disorders in Krebs cycle function and oxidative respiration (Sections 3.1 and 3.2). Metabolomics is an emerging research field in AD; its main purpose is to identify novel biomarkers of AD to facilitate the diagnosis of AD in the mild cognitive impairment (MCI) phase (Oresic et al., 2011; Czech et al., 2012; Mapstone et al., 2014; Trushina and Mielke, 2014). Currently, there are still many technical problems associated with this approach, e.g. metabolite identification, a large number of different metabolites, and standardization of sample preparation, commonly from plasma or cerebrospinal fluid (CSF) since postmortem brain samples are inappropriate. Trushina et al. (2013) observed that the Krebs cycle metabolite profile was significantly affected in the CSF samples of AD compared to that of MCI. The levels of many metabolites were reduced in the CSF of AD patients. They also reported that the levels of several Krebs cycle metabolites displayed mutation-specific changes in transgenic AD mice (Trushina et al., 2012). Although these studies indicate that there are defects in mitochondrial metabolome, they do not reveal the specific alterations at the neuronal level.

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3.1. Impaired Krebs cycle function

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The Krebs cycle, also known as the tricarboxylic acid or citric acid cycle, involves the enzymes which oxidize the compounds derived from the metabolism of fuel molecules, i.e. glucose, fatty acids and amino acids (Fig. 1). The Krebs cycle generates three reduced NADH and one FADH2 molecules, which are electron carriers and subsequently oxidized by O2 in the electron transport chain (Section 3.2). Krebs cycle intermediates, mainly 2-oxoglutarate and oxaloacetate, also provide carbon molecules for biosynthetic reactions, e.g. for amino acid and glutamate syntheses (Section 3.3). Many Krebs cycle enzymes function as multienzyme complexes, the activity of these complexes is controlled through allosteric mechanisms, e.g. that of 2-oxoglutarate dehydrogenase complex, but also by transcriptional and post-translational regulation (Sheu and Blass, 1999; Strumilo, 2005; Nunes-Nesi et al., 2013). The mitochondrial inner membrane is impermeable to Krebs cycle metabolites and thus there are carriers which enable both efflux and influx of Krebs cycle intermediates. The most important mitochondrial carriers are (i) 2-oxoglutarate carrier (OGC) which exchanges internal 2-oxoglutarate and succinate for external malate (Monne et al., 2013), (ii) citrate carrier (CiC) which transports citrate and isocitrate from mitochondria (Gnoni et al., 2009; Infantino et al., 2011), and (iii) dicarboxylate carrier (DIC) which transfers succinate and oxaloacetate across the mitochondrial inner membrane (Palmieri, 2004; Monne et al., 2013). These carriers have a crucial role during the dysfunction of Krebs cycle, since they transport the accumulating intermediates into the cytosol and thus they influence the control of 2-oxoglutaratedependent oxygenases (Section 4). There is an extensive literature indicating that the function of the major Krebs cycle enzyme complex, 2-oxoglutarate dehydrogenase (2-OGDH), earlier known as a-ketoglutarate dehydrogenase, was inhibited in the neurons of AD brain (Mastrogiacomo et al., 1993; Ko et al., 2001; Gibson et al., 2005; Bubber et al., 2005; Gibson et al., 2010). Transgenic AD mice also displayed a reduction in the function of 2-OGDH complex (Gibson et al., 1998a; Dumont et al., 2009). The 2-OGDH complex contains three different enzymes, (i) 2-oxoglutarate decarboxylase (E1), (ii) dihydrolipoamide succinyl transferase (E2), and (iii) dihydrolipoamide dehydrogenase (E3), which decarboxylate 2-oxoglutarate to succinylCoA (Sheu and Blass, 1999). Mastrogiacomo et al. (1993) observed that the protein levels of all three subunits were reduced by 23– 41% and the activity of the 2-OGDH complex by 56% in the temporal cortex of AD patients. Significant decreases were also present in the hippocampus and parietal cortex. Sheu et al. (1994) reported that the activity of 2-OGDH complex was also reduced in fibroblasts obtained from AD patients, with particularly the E2 component being affected. Interestingly, Dumont et al. (2009) reported that the heterozygotic deletion of dihydrolipoyl succinyltransferase (DLST)(E2) in the APP transgenic AD mice (Tg19959) significantly increased the level of amyloid-b oligomers and bamyloid plaques as well as caused an impairment of the spatial learning and memory in these mice. It is known that the 2-OGDH complex can be both the target and generator of ROS and thus it is a crucial cellular redox sensor (Tretter and Adam-Vizi, 2005; McLain et al., 2011). The lipoic acid, a cofactor of E2, is highly responsive to hydrogen peroxide and oxidative stress can induce a reversible glutathionylation of lipoic acid, which protects E2 against the inactivation of 2-OGDH by 4-hydroxy-2-nonenal (HNE), a product of lipid peroxidation (Applegate et al., 2008). Several studies have revealed that the levels of HNE and HNE-adducts were increased in AD brains (Reed et al., 2009; Butterfield et al., 2010). Sancheti et al. (2014) demonstrated that lipoic acid treatment could reverse the metabolic deficits, e.g. restore glucose metabolism, in triple transgenic AD mice. Moreover, Quinn et al. (2007) reported that a

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chronic dietary lipoic acid exposure reduced the appearance of memory impairment in Tg2576 mice, an AD model for the cerebral amyloidosis associated with AD. These studies indicate that the 2OGDO complex is a very sensitive target of oxidative stress, which is a common hallmark of AD pathogenesis (Su et al., 2008; Sultana and Butterfield, 2010). Experimental studies have revealed that the inhibition of 2OGDH activity, either genetically or with specific inhibitors, disturbed both neuronal energy metabolism and amino acid synthesis (Santos et al., 2006; Nilsen et al., 2011; Trofimova et al., 2012). Trofimova et al. (2012) reported that the treatment of cultured rat cerebellar neurons with succinyl phosphonate, an inhibitor of 2-OGDH, increased the accumulation of 2-oxoglutarate and pyruvate, indicating that the activity of the Krebs cycle had been inhibited. Moreover, they observed that the levels of alanine, glutamate and GABA were clearly increased denoting the increase in amino acid synthesis due to the increased supply of 2oxoglutarate (Section 3.3). Their results also indicated that glucose homeostasis was stabilized concomitantly with the deficiency of Krebs cycle. Nilsen et al. (2011) observed that the deletion of dihydrolipoyl succinyltransferase (DLST)(E2), a key component of 2-OGDH, also reduced the use of glucose in mouse brain. These studies imply that disturbances in Krebs cycle impair as a negative feedback the glucose metabolism in the brain. Mounting evidence from imaging studies indicates that the progressive decline in glucose metabolism is an early diagnostic parameter of AD dementia (Mosconi, 2005; Yao et al., 2011b; Chen and Zhong, 2013). Cholinergic brain regions are the most vulnerable to glucose hypometabolism. Interestingly, the level of 2-OGDH complexes is clearly enriched in cholinergic neurons, e.g. in rat hippocampal pyramidal CA1 and CA2 layers (Calingasan et al., 1994). Moreover, Ko et al. (2001) revealed that the 2-OGDH-enriched neurons are especially affected in AD brain. This points to a scenario where the 2-OGDH-driven dysfunction of Krebs cycle is linked to reduced glucose utilization generating a vicious cycle inside cholinergic neurons eventually leading to their degeneration. Bubber et al. (2005) demonstrated that although there was a clear decrease in the activity of 2-OGDH ( 57%), the activities of succinate dehydrogenase (SDH) (+44%) and malate dehydrogenase (+54%) were significantly increased whereas those of aconitase, isocitrate dehydrogenase and fumarase were unaffected in the prefrontal cortex of AD patients. They also observed that the activity of the pyruvate dehydrogenase complex was reduced in AD brains, indicating that there would be a defect in the supply of acetyl-CoA from glycolysis to the Krebs cycle. The increase in the activity of succinate dehydrogenase is an interesting observation since it is known that the activity of succinate dehydrogenase is inhibited by amyloid-b (Kaneko et al., 1995) and APP containing the Kunitz domain (Chua et al., 2013). The increase in the activity of SDH in AD brains could be linked to the presence of local hypoxia (Section 6), since many studies have indicated that chronic hypoxia increased the activity of SDH, e.g. in mouse cerebral cortex (Caceda et al., 2001) and liver (Kinnula, 1975). There is also evidence that hypoxia stimulated the accumulation of succinate, a substrate for SDH, in the mitochondria of several tissues (Chinopoulos, 2013). Thus, the increased activity of SDH could attempt to oppose the accumulation of succinate in AD brains, since it is known that succinate could inhibit the 2-OGDO enzymes and enhance stochastic DNA and histone methylation (Sections 4.1 and 4.2). Interestingly, SIRT3 increased the activity of SDH complex by deacetylating the SDHA subunit in mammalian mitochondria (Cimen et al., 2010; Finley et al., 2011) (Section 4.4). Recently, Weir et al. (2012) reported that increased mitochondrial production of ROS increased the expression of SIRT3 in cultured mouse hippocampal neurons. They also observed that the expression of SIRT3 was up-regulated in the brains of AD patients and transgenic

AD mice overexpressing amyloid-b. These studies imply that succinate may well be harmful for neurons and should be removed by increasing the activity of SDH, probably for its role in epigenetic regulation of chromatin landscape.

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3.2. Decline in oxidative phosphorylation

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Oxidative phosphorylation (OXPHOS) involves the transfer of electrons from reduced NADH and FADH2 to molecular oxygen, a pathway which consequently generates ATP from ADP. This process occurs in the electron transport chain including four respiratory complexes (I–IV) and an ATP synthase complex, located in the inner mitochondrial membrane (Lenaz and Genova, 2010). Disturbances in OXPHOS exert many effects on cellular homeostasis, e.g. (i) reductions in ATP production, (ii) augmentation in ROS production, and (iii) promoting the accumulation of NADH and FADH2 in mitochondria. The elevation of NADH and ROS levels in mitochondria inhibits the activities of Krebs cycle enzymes and consequently triggers the accumulation of distinct Krebs cycle intermediates, a process which subsequently can modify the activities of 2-OGDO enzymes and disturb neuronal function (Section 4). Moreover, impaired OXPHOS can disrupt mitochondrial dynamics provoking mitochondrial fragmentation and neurodegeneration (Moran et al., 2012). Over twenty years ago, it was observed that the activity of cytochrome c oxidase (complex IV) was significantly decreased in the brain regions affected by AD (Kish et al., 1992; Simonian and Hyman, 1993; Parker et al., 1994; Chandrasekaran et al., 1998). Nagy et al. (1999) examined AD brains with immunohistochemistry and demonstrated that the hippocampal neurons containing neurofibrillary tangles had very low levels of cytochrome c oxidase, whereas healthy, tangle-free nearby neurons even displayed an increased level of cytochrome c oxidase. It was also revealed that dystrophic neurites of senile plaques were lacking of cytochrome c oxidase (Perez-Gracia et al., 2008). Xie et al. (2013) observed in transgenic AD mice that mitochondria in the neurons close to b-amyloid plaques were gradually fragmented and showed a reduced expression of subunit 4 in the cytochrome c oxidase complex (complex IV). Accordingly, the mitochondrial membrane potential was considerably reduced indicating that the efficiency of respiratory chain and consequently, ATP synthesis were significantly impaired in these neurons. It seems that complex IV, and especially its subunit 4, is the most affected respiratory complex in AD brains, although there are studies indicating that complex I could also be impaired in transgenic AD mice (Rhein et al., 2009). The mechanism of AD-associated decline in the efficiency of OXPHOS is still elusive and moreover, defective OXPHOS has been observed in several age-related diseases (Fosslien, 2001). It is clear that respiratory complexes are both the targets of ROS and the generators of ROS (Musatov and Robinson, 2012). In AD, there are reports indicating that amyloid-b can induce ROS production in neuronal mitochondria and disturb the function of complex IV (Bobba et al., 2013b). Canevari et al. (1999) observed that the amyloid-b fragment 25–35 decreased the activity of complex IV but did not affect the activity of the other respiratory complexes in isolated rat brain mitochondria. Moreover, the hypoxia-induced oxidative stress stimulated the sequestration of protein kinase A from the mitochondrial outer membrane to the inner membrane, where the respiratory complexes are located (Srinivasan et al., 2013). Prabu et al. (2006) revealed that protein kinase A induced the phosphorylation of distinct subunits of complex IV thus provoking their degradation and the decline of complex IV activity. Interestingly, Samavati et al. (2008) demonstrated that cytokine TNFa induced the phosphorylation of subunit 1 in complex IV; this inhibited the activity of complex IV, and subsequently reduced ATP synthesis in murine hepatocytes. It is known that a low-grade

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inflammation is linked to AD, but it is not known whether it provokes the inhibition of OXPHOS in AD. Given that the inhibition of OXPHOS will trigger the accumulation of NADH, which is a powerful allosteric inhibitor of NAD+-dependent 2-OGDH and isocitrate dehydrogenase in the Krebs cycle, it seems that a reduced OXPHOS in AD could induce the accumulation of 2oxoglutarate and citrate, which are two potent epigenetic regulators (Section 4).

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3.3. Anaplerosis and cataplerosis

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Krebs cycle intermediates can be replenished from other metabolic reactions or they can exit from the cycle, both of these events can affect the function of the Krebs cycle. The term anaplerosis refers to the entry of intermediates into the cycle, whereas cataplerosis denotes the exit of intermediate compounds so that they can be used in other metabolic processes (Owen et al., 2002) (Fig. 1). It is important to remember that anaplerotic and cataplerotic pathways are highly cell- and organ-specific processes, which have not been well clarified in the neurons or brain. Krebs cycle intermediates are not only substrates for energy production but also compounds for e.g. neurotransmitter and non-essential amino acid syntheses (Owen et al., 2002; Araujo et al., 2013). On the other hand, these reactions tend to be reversible, i.e. if there is a deficiency in the glucose/pyruvate supply, then amino acids and even neurotransmitters, e.g. glutamate and GABA, can be converted into Krebs cycle intermediates to maintain energy metabolism. Glutamate, an activating neurotransmitter in glutamatergic neurons, can be synthesized via transamination reactions from 2-oxoglutarate (Kovacevic and McGivan, 1983; Kvamme, 1998). In contrast, the enzyme glutamate dehydrogenase (GDH) converts glutamate to 2-oxoglutarate in the anaplerotic reaction (Plaitakis and Zaganas, 2001; Li et al., 2012). Several important amino acids, such as glutamine, alanine, arginine and proline, can be metabolized to 2-oxoglutarate via anaplerotic glutamate pathway (Owen et al., 2002; Trofimova et al., 2012). Moreover, GABA, an inhibitory neurotransmitter, can be synthesized from glutamate in a decarboxylation reaction, and subsequently GABA can be converted to succinate (Fig. 1). The pathway from 2oxoglutarate to succinate via glutamate and GABA is called the GABA shunt (Hassel et al., 1998; Yogeeswari et al., 2005). Thus, it is possible for the GABA shunt to bypass the 2-OGDH enzyme in the function of Krebs cycle. Trofimova et al. (2012) demonstrated that the inhibition of 2-OGDH with succinyl phosphonate in cultured neurons increased the level of 2-oxoglutarate and pyruvate but not of succinate or fumarate. In addition, the concentrations of glutamate and GABA were increased as well as many non-essential amino acids, such as alanine, asparagine, glycine and proline. These studies indicate that in the case of the inhibition of 2-OGDH, e.g. as may occur in AD pathology (Section 3.1), 2-oxoglutarate could be directed to alternative routes, possibly to generate energy via the GABA shunt but this would simultaneously expose neurons to harmful epigenetic effects on chromatin methylation status (Section 4.2) (Fig. 1). Another important cataplerotic pathway is the export of citrate from the Krebs cycle and its consequent conversion to acetyl-CoA in the cytosol (Fig. 1). Acetyl-CoA has a fundamental role in the control of metabolism via acetylation reactions in many cellular compartments (Cai and Tu, 2011; Newman et al., 2012). AcetylCoA is produced in mammalian mitochondria in several pathways; (i) mostly from pyruvate generated in glycolysis, but also (ii) from ketone bodies, i.e. acetoacetate and b-hydroxybutyrate (Newman and Verdin, 2014), and (iii) from acetate through synthesis with acetyl-CoA synthetase 2 (Fujino et al., 2001). Subsequently, citrate synthase incorporates acetyl-CoA into the Krebs cycle catalyzing the synthesis of citrate. Citrate is a substrate for aconitase in the

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Krebs cycle, but citrate can also be transported into cytoplasm via the citrate carrier (CIC) (Gnoni et al., 2009). In cytosol, ATP-citrate lyase (ACL) converts citrate back to acetyl-CoA and it is consumed in many acetylation reactions in several subcellular locations, i.e. cytoplasm, endoplasmic reticulum, and nucleus (Chypre et al., 2012; Icard et al., 2012). For instance, acetyl-CoA is required for many synthetic reactions, e.g. fatty acid synthesis (Wakil et al., 1983) and the production of the neurotransmitter acetylcholine in the cholinergic neurons (Szutowicz et al., 2013). There are also reports that the acetylation of the tau K280 motif has enhanced the aggregation of tau protein and the level of acetylated K280 was increased in AD brains (Irwin et al., 2012). On the other hand, Cook et al. (2014) demonstrated that the acetylation of the KXGS motif, not related to K280, could prevent the hyperphosphorylation of this site in tau protein and inhibited its aggregation. They revealed that this lysine site was hypoacetylated in AD patients and thus prone to hyperphosphorylation. Histone deacetylase 6 (HDAC6) is responsible for the deacetylation of these tau residues and thus for increased tau polymerization. These observations imply that there might be disturbances in the metabolic regulation of the cataplerotic citrate/acetyl-CoA pathway in the AD brain. Since anaplerotic and cataplerotic reactions linked to the Krebs cycle can regulate the synthesis of neurotransmitters, it is possible that disturbances in Krebs cycle function could be reflected in defects in neurotransmitter synthesis in AD patients. There is an abundant literature indicating that the regulation of glutamatergic, GABAergic and especially cholinergic activities is clearly impaired in AD (Butterfield and Pocernich, 2003; Lanctot et al., 2004; Craig et al., 2011; Revett et al., 2013; Szutowicz et al., 2013). Since it is not feasible to record the levels of energy metabolites in the postmortem brain samples, the research has tended to focus on the receptors and signaling mechanisms. Glutamate is not only synthesized from 2-oxoglutarate but also glutamine can be converted to glutamate by the enzyme glutaminase. Moreover, perisynaptic astrocytes take up synaptic glutamate and convert it to glutamine, which is secreted and transported to neurons. This is called the glutamate-glutamine cycle (McKenna, 2007). Astrocytes are also involved in the synthesis of GABA, which can also be produced from glutamine (Schousboe et al., 2013). Glutamate and GABA are important neurotransmitters which participate in learning and memory formation and thus defects in Krebs cycle function could provoke cognitive decline and dementia in AD patients. There are clear indications that disturbances in acetylCoA homeostasis could be able to induce the degeneration of cholinergic neurons in AD brain (Szutowicz et al., 2013). The effects of deficient acetylcholine secretion can be prevented by treatment with acetylcholinesterase inhibitors in AD therapy. A more detailed discussion on the role of Krebs cycle in the synthesis of neurotransmitters is beyond the scope of this review. In summary, it seems that although the AD-related dysfunction of the Krebs cycle can directly impair neurotransmitter synthesis, there are also some indications that Krebs cycle metabolites can affect cognitive decline through the shaping of chromatin landscape (Sections 5 and 6).

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4. Energy metabolites control the epigenetic landscape of chromatin

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DNA methylation in cooperation with histone acetylation and methylation are the most fundamental chromatin modifications, which control gene transcription along with many other nuclear functions, e.g. the maintenance of chromatin organization and celltype specific DNA memory (Bird, 2002; Shahbazian and Grunstein, 2007; Li and Reinberg, 2011; Rose and Klose, 2014). This is commonly called epigenetic regulation since it is independent of the changes in DNA sequence. In the brain, the epigenetic control of

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chromatin landscape is crucially involved in many developmental processes (Fagiolini et al., 2009) as well as in the regulation of learning and memory (Gra¨ff and Tsai, 2013; Zovkic et al., 2013) and several psychiatric and neurological disorders, e.g. schizophrenia and AD (Gra¨ff et al., 2011; Peter and Akbarian, 2011). The status of DNA and histone methylation is maintained by methyltransferases and demethylases, whereas histone acetylation is regulated by histone acetyltransferases and deacetylases. Recent studies have indicated that the chromatin is an epigenetically regulated information platform, which integrates different signaling mechanisms, e.g. signal transduction pathways and non-coding RNAs, in order to control responses to external and internal stimuli (Suganuma and Workman, 2011; Badeaux and Shi, 2013). Emerging studies have revealed that the mitochondrial energy metabolism, i.e. Krebs cycle function, can control the epigenetic landscape of chromatin and thus regulate gene expression and if impaired, this can trigger serious pathological events, e.g. many cancers (Wellen and Thompson, 2012; Kaelin and McKnight, 2013; Benit et al., 2014; Salminen et al., 2014a,b). Several cancer studies have revealed that the inhibition of succinate dehydrogenase and fumarate hydratase induces the accumulation of succinate and fumarate and subsequently leads to DNA hypermethylation and the appearance of certain cancers (Section 4.2). Mechanistic studies have demonstrated that the cellular deposition of succinate and fumarate pool can inhibit the 2-OGDO enzymes, which are activated by 2-oxoglutarate, a crucial metabolite of Krebs cycle (Section 3). Interestingly, it has been demonstrated that the key enzymes of DNA and histone demethylation are included in the 2OGDO family, and thus under the regulation by Krebs cycle metabolites (Sections 4.1 and 4.2) (Fig. 3).

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4.1. 2-Oxoglutarate-dependent oxygenases

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The family of 2-OGDO enzymes consists of a large group of evolutionarily-conserved, heme-independent hydroxylases (Hausinger, 2004; Clifton et al., 2006; McDonough et al., 2010). These enzymes can oxidize a variety of targets, including distinct amino acid residues, e.g. lysine, asparagine and proline as well as methylated lysine and methylated cytosine. According to their target specificity, it is possible to distinguish different subfamilies of 2-OGDO enzymes, such as DNA and histone demethylases, which are crucial enzymes controlling the epigenetic landscape of

chromatin (Klose et al., 2006; Pastor et al., 2013) (Section 4.2). Moreover, the 2-OGDO family includes several important enzymes linked to non-epigenetic regulation, such as proline hydroxylases controlling collagen metabolism and hypoxic responses (Kivirikko et al., 1989; Myllyharju, 2013). With respect to AD, prolyl 4hydroxylases (PHD1-3) have a significant role since they control in an oxygen-dependent manner the activity of hypoxia-inducible factor-1a (HIF-1a). There are many reports which indicate that hypoxia can facilitate AD pathogenesis (Zhang and Le, 2010). For instance, HIF-1a induces the expression of BACE1 and accordingly stimulates the production of amyloid-b42 (Guglielmotto et al., 2009). The reaction of 2-OGDO enzymes couples the substrate hydroxylation/demethylation with the O2-dependent decarboxylation of 2-oxoglutarate into succinate and CO2 (Fig. 3). The oxidative reaction is catalyzed by Fe(II), ferrous iron, which is oxidized to Fe(IV). Vitamin C is required to reduce Fe(IV) to Fe(II) in order to restore the activity of 2-OGDO enzymes (Monfort and Wutz, 2013). This means that the cellular redox status can control the activity of 2-OGDO enzymes. Several transition metals, e.g. cobalt, copper and zinc, are potent inhibitors of 2-OGDO enzymes (Sekirnik et al., 2010; Rose et al., 2011). The catalytic domain of 2OGDO enzymes contains modified eight-fold b-sheets, also called jelly-roll folding (Aik et al., 2012). This core structure contains the binding sites for 2-oxoglutarate and Fe(II). In histone demethylases, this structure has been termed as the Jumonji C domain (Klose et al., 2006). The structural and functional details have been described more thoroughly elsewhere (McDonough et al., 2010; Aik et al., 2012). Interestingly, there are many reports claiming that iron metabolism is impaired in AD (Castellani et al., 2012; Ayton et al., 2013; Schro¨der et al., 2013) and furthermore, many transition metals have been implicated in AD pathogenesis (Shcherbatykh and Carpenter, 2007; Ayton et al., 2013). Currently, it is still not clear whether the metal dyshomeostasis present in AD could modify the epigenetic landscape of chromatin by affecting DNA and histone demethylases.

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4.2. Krebs cycle metabolites regulate DNA and histone methylation

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There are seven subfamilies of histone lysine demethylases (KDM) of which six (KDM2-7) are included in the 2-OGDO family containing the Jumonji C domain (Klose et al., 2006; Johansson

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Fig. 3. A diagram showing the regulation of DNA and histone methylation through the 2-OGDO enzymes TET1-3 and KDM2-7. The Krebs cycle intermediate, 2-oxoglutarate, is the substrate of these enzymes and the Fe(II/IV) redox balance and O2 level control the activity of 2-OGDO enzymes. The enzyme reaction produces succinate, which is an inhibitor of 2-OGDO enzymes. Krebs cycle dysfunction, local hypoxia and iron imbalance are associated with AD.


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et al., 2014). Individual KDM2-7 enzymes specifically recognize distinct histone methylation sites, e.g. KDM4 and KDM6 demethylate repressive histone marks H3K9 and H3K27, respectively, whereas KDM5 and KDM2 remove methyl groups from the activating sites, H3K4 and H3K36 (Johansson et al., 2014). The KDM proteins contain different protein-protein interaction domains and posttranslational modification sites, which provide the functional specificity for histone demethylation. Recently, Tahiliani et al. (2009) revealed that Ten-Eleven Translocation 1-3 (TET1-3) enzymes could hydroxylate the 5mC residues to 5-hydroxymethylcytosine (5hmC) and thus triggered the demethylation process in mammalian DNA (Pastor et al., 2013). Tahiliani et al. (2009) also demonstrated that TET1-3 enzymes were included in the 2-OGDO family and thus the demethylation process was dependent on 2-oxoglutarate and Fe(II) (Fig. 3). Interestingly, the highest levels of 5hmC are present in the brain, particularly in the neurons of the cerebral cortex (Kriaucionis and Heintz, 2009; Globisch et al., 2010). Given that 2-oxoglutarate is an obligatory substrate for the function of 2-OGDO enzymes, this means that the epigenetic regulation of DNA and histone methylation is dependent on the presence of 2-oxoglutarate, a key energy metabolite produced in mitochondria, either via the Krebs cycle or by the deamination of glutamate (Section 3). There are specific carrier proteins for 2oxoglutarate in the mitochondrial inner membrane (Monne et al., 2013), whereas 2-oxoglutarate cannot penetrate into cells through cell surface. Many studies have demonstrated that succinate and fumarate, also Krebs cycle intermediates, can bind to the 2oxoglutarate site in the 2-OGDO enzymes, but they are not suitable substrates for enzyme activity (Rose et al., 2011; Xiao et al., 2012). This means that they are competitive inhibitors of the 2-OGDO enzymes (Fig. 1). Xiao et al. (2012) demonstrated that succinate and fumarate inhibited the activities of many different KDMs in vitro assays, even at the physiological concentration levels. Using cell culture experiments, they demonstrated that the cellpermeable methyl-succinate and methyl-fumarate increased the genome-wide histone methylation. Interestingly, the levels of both activating epigenetic mark, H3K4me1, and repressive mark, H3K27me2, were increased in 293T and HeLa cells. These responses could be attenuated through the exposure of cellpermeable 2-oxoglutarate, indicating that succinate and fumarate were competitive inhibitors to KDMs. They also confirmed that the depletion of SDHA/B and fumarate hydratase (FH) transcripts by siRNA increased the levels of succinate and fumarate in HeLa cells. Cervera et al. (2009) also demonstrated that the inhibition of SDH expression by pharmacological or siRNA techniques globally increased both the activating and repressive epigenetic marks. The methylation of H3K27me3 could be reversed by the overexpression of JMJD3 (KDM6B), a specific demethylase of H3K27. Xiao et al. (2012) also revealed that suppression of SDH and FH expression robustly decreased the TET-catalyzed production of 5hmC in cultured cells. Moreover, they reported that the transient knockdown of SDHA and FH in mouse liver led to the accumulation of intracellular succinate and fumarate along with increased levels of H3K4me1, H3K4me3, H3K9me2, and H3K27me2. The quantity of 5hmC was also down-regulated in the knockdown livers (Xiao et al., 2012). These results indicate that Krebs cycle intermediates can control the DNA and histone methylation status in cultured cells and even in tissues. However, it is worthwhile noting that the succinate and fumarate-induced histone hypermethylation targeted both the activating and repressive epigenetic marks, probably also excessive 2-oxoglutarate might have global demethylating effects. Recent molecular studies have demonstrated that the oncogenic mutations of SDH and FH genes in humans increase the accumulation of succinate and fumarate and consequently

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increase the global methylation of DNA and histones in tissues (Killian et al., 2013; Letouze et al., 2013; Yang et al., 2013). These metabolites have been given the name of oncometabolites (Yang et al., 2013). In addition, mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and 2) convert isocitrate, a Krebs cycle metabolite, to R( )-2-hydroxyglutarate, instead of 2-oxoglutarate (Xu et al., 2011; Cairns and Mak, 2013). R( )-2-hydroxyglutarate is a competitive inhibitor of 2-OGDO enzymes and thus it is also an oncometabolite. Letouze et al. (2013) and Killian et al. (2013) demonstrated that the cancers induced by mutations in SDH were associated with significant DNA hypermethylation, indicating that the TET enzymes had been inhibited. Letouze et al. (2013) confirmed that there was a 100-fold increase in the succinate concentration in the cancer tissues of SDH mutants. Moreover, the epigenetic changes were linked to profound alterations in gene expression profiles. It seems that disturbances in Krebs cycle function can induce apparently random changes in DNA and histone methylation, which could lead to a stochastic epigenetic drift in gene expression, e.g. in cancer (Landan et al., 2012) as well as in AD and aging process (Martin, 2012).

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4.3. Acetyl-CoA-related pathways regulate histone acetylation

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The acetylation of lysine residues within the N-terminal part of histones is an obligatory modification in the activation of gene transcription. Histone acetyltransferases (HAT) catalyze the acetylation reaction and consequently generate an open euchromatin state, whereas histone deacetylases (HDAC) remove the acetyl group and induce heterochromatin formation. There is a partial site-specificity between the different acetyltransferases in the acetylation of histones (Shahbazian and Grunstein, 2007). Acetyl-CoA is an obligatory metabolite in histone acetylation and thus an important link between metabolism and epigenetic modification of chromatin landscape (Cai and Tu, 2011; Katada et al., 2012). In 2009, Wellen et al. revealed that the cytoplasmic acetyl-CoA citrate-lyase (ACL) converted the citrate transported from mitochondria to acetyl-CoA, which was subsequently used by HATs to increase histone acetylation (Fig. 1). They also observed that glucose metabolism was linked via glycolysis to histone acetylation in an ACL-dependent manner. These observations indicated that energy metabolism has a fundamental role in the control of histone acetylation through the citrate-induced ACL activation. On the other hand, they demonstrated that the histone acetylation triggered by ACL was associated with the activation of gene expression controlling energy metabolism, e.g. glucose uptake. Given that acetyl-CoA is also required for many synthetic reactions, Galdieri and Vancura (2012) reported that the inhibition of acetyl-CoA carboxylase, a key enzyme in fatty acid synthesis, induced global histone acetylation. This is evidence that disturbances in energy metabolism, particularly in the regulation of citrate/acetyl-CoA homeostasis, could affect the epigenetic regulation of chromatin. Moreover, there are observations that ACL can suppress the expression of DNA methyltransferase 1 (DNMT1) by promoting the expression of miR-148a in an acetyl-CoA-dependent manner (Londono Gentile et al., 2013). This indicates that acetyl-CoA also affects the regulation of DNA methylation by controlling DNMT1 expression. There are reports that mitochondria may be involved in the histone acetylation via distinct other mechanisms in addition to the citrate/acetyl-CoA pathway. Madiraju et al. (2009) revealed that mitochondrial acetylcarnitine was transported to the cytoplasm via carnitine/acylcarnitine translocase and subsequently, was converted to acetyl-CoA and carnitine in the nuclei. Recently, Nasca et al. (2013) demonstrated that acetylcarnitine could exert antidepressant effects by enhancing the expression of type 2 metabotropic glutamate (mGlu2) receptor in the hippocampus

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of spontaneously depressed Flinders Sensitive Line rats. Acetylcarnitine exposure increased the level of K27-acetylated H3 histones in the promoter of mGlu2 receptor gene Grm2, indicating that acetylcarnitine generates epigenetic modifications. Moreover, Sutendra et al. (2014) revealed that the components of pyruvate dehydrogenase complex (PDC) could be transported from the mitochondria to the nucleus, where they produced acetyl-CoA from pyruvate for the acetylation reactions, e.g. those of core histones. The nuclear transport of PDC was enhanced by mitochondrial stress, e.g. induced by rotenone. Given that the function of Krebs cycle is compromised in AD brains, this could be associated with the hypoacetylation of histones in AD brains (Section 5).

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4.4. NAD+ and FAD+-dependent regulation of the epigenetic landscape

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Nicotinamide adenine dinucleotides (NAD+) and flavin adenine dinucleotides (FAD+) are the electron carriers for respiratory chain inside the mitochondria but they are also cofactors for many NAD+/ FAD+-dependent enzymes. Both NAD+ and FAD+ are compartmentalized into different cellular pools, i.e. into the mitochondrial and cytosolic/nuclear pools (Chiarugi et al., 2012; Giancaspero et al., 2013). Although NAD+/FAD+ cannot be transported through the inner mitochondrial membrane, disturbances in mitochondrial oxidative respiration affect the cytosolic redox ratio of NAD+/ NADH and FAD+/FADH2 and thus can also control the activities of NAD+/FAD+-dependent enzymes, e.g. silent information regulators (Sirtuins/SIRTs) and lysine-specific demethylase 1 (LSD1), outside of mitochondria. Sirtuins (SIRT1-7) are NAD+-dependent histone deacetylases, of which SIRT3-5 are located in the mitochondria whereas SIRT1, SIRT6 and SIRT7 are nuclear enzymes (Michan and Sinclair, 2007). SIRT3 and SIRT5 are important mitochondrial regulators of enzyme acetylation and also succinylation (SIRT5) and in that way they control both mitochondrial and cellular metabolism (He et al., 2012; Park et al., 2013b). For instance, SIRT3 regulates intermediate metabolism by enhancing the activity of acetyl-CoA synthetase 2 and thus increasing the production of acetyl-CoA. Moreover, it can activate Krebs cycle enzymes IDH2 and SDHA, which control Krebs cycle function and thus indirectly affect epigenetic regulation (Sections 4.2 and 4.3). SIRT5 is a potent desuccinylase and it is involved many mitochondrial metabolic pathways, e.g. the Krebs cycle (Du et al., 2011; Park et al., 2013b). Weir et al. (2012) demonstrated that oxidative stress increased the activity of SIRT3 in mouse hippocampal neurons. Moreover, they reported that the activity of SIRT3 was increased in the hippocampus of transgenic AD mice as well as in the temporal cortex of AD patients. This might indicate a protective adaptation against mitochondrial stress in AD. Given that SIRT3 improves mitochondrial energy metabolism, it has important responses to both healthspan and lifespan (Giralt and Villarroya, 2012; He et al., 2012). Nuclear SIRTs can remove the acetyl group not only from histones but also from a variety of other proteins, e.g. transcription factors (Michan and Sinclair, 2007; Kim and Kim, 2013; Kugel and Mostoslavsky, 2014). Currently, it seems that nuclear SIRTs control the histone acetylation of certain specific lysine sites at distinct gene promoters, whereas class I and II HDACs are more global histone deacetylases. SIRT1 and SIRT6 have distinct and specific functions in chromatin regulation, e.g. circadian regulation (SIRT1), telomere maintenance and DNA repair (SIRT6) (Bellet and SassoneCorsi, 2010; Kugel and Mostoslavsky, 2014). Moreover, SIRT1 and SIRT6 have fundamental roles in the regulation of metabolism, e.g. mitochondrial energy metabolism (Michan and Sinclair, 2007; Guarente, 2008; Zhong and Mostoslavsky, 2010), and in this way they could affect acetyl-CoA synthesis and Krebs cycle function (Sections 4.2 and 4.3). One control mechanism could be the

competition between SIRTs and poly(ADP-ribose)-polymerases (PARPs) in the use of nuclear NAD+ pool since both enzymes are dependent on the presence of NAD+. PARP-1 transfers the ADPribose group from NAD+ to target molecules thus reducing the nuclear level of NAD+ (Kim et al., 2005). Many stresses, e.g. DNA damage, can deplete nuclear NAD+ storage and downregulate the function of SIRTs. Love et al. (1999) reported that the poly(ADPribosyl)ation of nuclear proteins was increased in AD, particularly in pyramidal neurons, which implies that there could be a deficiency of NAD+ in affected neurons. This is in accordance with many observations that SIRT1 seems to protect against neuronal injuries in AD (Bonda et al., 2011). FAD+ is a redox factor which has several functions in cellular metabolism, e.g. as an electron carrier and cofactor of many enzymes (Barile et al., 2013). Forneris et al. (2005) demonstrated that LSD1 is an FAD+-dependent histone demethylase, evidence that energy metabolism can affect the epigenetic landscape of chromatin. LSD1 is a lysine-specific demethylase targeting the methylated H3K4 site, an activating epigenetic mark. Hino et al. (2012) revealed that the activation of LSD1 repressed the expression of several energy metabolic regulators, e.g. PPARg coactivator-1a (PGC-1a), whereas the loss of LSD1 induced their expression and stimulated mitochondrial metabolism in adipocytes. They also reported that the depletion of FAD+ reduced the activity of LSD1 and its metabolic responses. Zhang et al. (2010) observed that LSD1 was concentrated in the nuclei of neurons in rat hippocampus and cerebral cortex. They also revealed that transient global cerebral ischemia strongly increased the expression of LSD1, which might attenuate gene transcription and thus affect mitochondrial metabolism. Given that NAD+ and FAD+ have such fundamental roles in energy metabolism and disturbances in their level are involved in many diseases (Magni et al., 2008; Barile et al., 2013), it seems that SIRT1 and LSD1 could enhance the maintenance of energy metabolic homeostasis through epigenetic regulation.

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5. Epigenetic changes in AD

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There is extensive evidence indicating that epigenetics has a crucial role in the pathogenesis of several diseases and it could explain the non-genetic origin of many degenerative diseases. The epigenetic landscape of chromatin is regulated by a variety of environmental exposures, during both prenatal and postnatal life, such as pathogenic and toxic insults, diverse stresses and many lifestyle factors, e.g. diet, exercise, and smoking (Alegria-Torres et al., 2011; Tammen et al., 2013). An epigenetic basis has also been proposed for several psychiatric disorders and neurodegenerative diseases (Babenko et al., 2012; Pena et al., 2014). Comparing extensive genome-wide genetic screening in AD, epigenetic largescale studies are currently topic receiving much interest. In 2010, Mastroeni et al. used immunohistochemistry to demonstrate that the level of DNA methylation (5mC) was significantly lower in the neurons of entorhinal cortex in AD patients than in normal agematched persons. They also reported that the immunoreactivity of DNA methyltransferase 1 (DNMT1) and several distinct components of methylated DNA binding complexes, e.g. MBD2/3 and MTA2, were down-regulated in the neurons of AD patients. Mastroeni et al. (2009) also revealed that the level of 5mC was significantly reduced in the neurons of temporal neocortex in the monozygotic twins, which were discordant for AD. Chouliaras et al. (2013) also observed that the global levels of both 5mC and 5hmC were significantly reduced in the affected hippocampal regions in AD patients, in both neurons and glial cells. In contrast, Coppieters et al. (2014) utilized the same technique but reported that the global levels of 5mC and 5hmC were significantly increased in the middle frontal gyrus and middle temporal gyrus, compared to

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age-matched controls. The AD-associated DNA hypermethylation was predominantly located in neurons and the level positively correlated with typical AD markers, i.e. amyloid plaques and tau tangles. Moreover, 5mC levels were clearly lower in glial cells than in neurons. In spite of these contradictory results on DNA methylation status, both of these studies do reveal that epigenetic methylation levels and responses are clearly cell type dependent, which complicates tissue level molecular screening studies. In the triple-transgenic mouse model of AD, Cadena-Del-Castillo et al. (2014) observed that the level of 5mC decreased with aging, especially in transgenic mice, whereas that of 5hmC was dramatically increased in affected brain regions. The nonspecificity of antibodies for 5mC and 5hmC may have disturbed these early immunohistochemical observations. Several studies have focused on the changes in gene-specific DNA methylation profiles, particularly in the promoters, between AD and age-matched control samples. Wang et al. (2008b) studied the GC-rich regions of potential AD risk genes, e.g. APOE, APP, BACE1, and PSEN1, in both the brain and blood samples of lateonset AD patients. They observed that there was extensive interindividual variability in DNA methylation patterns and the changes observed in the brain samples could not be repeated in blood lymphocytes. They could not find any gene with a common up- or down-regulation in their promoter methylation; instead they observed bimodal changes in promoters, i.e. distinct CpG sites which were either hypo- or hypermethylated in the late-onset AD. APOE and TFAM genes displayed similar divergent methylation patterns. It is known that in addition to APOE, the polymorphism of the TFAM gene, mitochondrial transcription factor A, has been associated with AD (Bertram et al., 2007). Rao et al. (2012) observed that DNA methylation was globally increased in the frontal cortex of AD patients, whereas the promoters of COX-2 and NF-kB/p50 and p65 were hypomethylated and their mRNA expression was increased in AD brain. Siegmund et al. (2007) screened the DNA methylation patterns of CpG islands in the promoters of 50 genes associated with CNS growth and development in human cerebral cortex. They observed that the DNA methylation profiles were dynamically regulated throughout the lifespan and reported that the methylation patterns of only two genes were associated with AD; the methylation of SORBS3 promoter increased, whereas that of S100A2 decreased in AD. Recently, Iwata et al. (2014) observed an aberrant methylation pattern in the CpG islands of APP, MAPT, and GSK3B genes in the temporal lobe samples of sporadic AD. The nuclear sorting of postmortem brain samples revealed that the abnormal methylation of APP and MAPT genes originated from both neuronal and nonneuronal nuclei, whereas the aberrant GSK3B methylation pattern was attributable to the non-neuronal cells. They also reported that an increase in the methylation of CpG sites enhanced the expression of APP gene but decreased the expression of MAPT gene. Interestingly, their results also indicated that it was only a small number of highly methylated neurons which contributed to the difference in the CpG site methylation of whole brain samples. This observation supports the hypothesis that a disturbance in energy metabolism of distinct individual neurons can switch on a stochastic series of epigenetic modifications, leading to synaptic loss and even neuronal death. Moreover, in addition to APP, MAPT, and GSK3B, many other genes associated with AD pathogenesis can be regulated by epigenetic mechanisms, e.g. clusterin (Rosemblit and Chen, 1994), presenilin 1 (Fuso et al., 2011), progranulin (Banzhaf-Strathmann et al., 2013), neuroligin 1 (Bie et al., 2014), a-synuclein (Matsumoto et al., 2010), neprilysin (Usmani et al., 2000), and transthyretin (Kerridge et al., 2014). However, it should be noted that many epigenetic screening studies on AD brains have not revealed any changes in the methylation patterns of these genes.

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Bakulski et al. (2012) analyzed the genome-wide DNA 1104 methylation patterns of the frontal cortex from the control and 1105 late-onset AD patients using the Illumina Infinium HumanMethy- 1106 lation27 BeadArray. They revealed that the 948 CpG sites out of 1107 27,578 detected, mostly in promoters, were potentially related to 1108 AD. The CpG sites which were most significantly associated with 1109 AD were located in TMEM59, ATG10, and RelB genes. However, 1110 many genes implicated in AD pathogenesis were not present in the 1111 genes differentially methylated in AD. Recently, De Jager et al. 1112 (2014) and Lunnon et al. (2014) identified several differentially 1113 methylated CpG sites in AD brains using the Illumina 450 K array. 1114 Both of these studies revealed that the Ankyrin 1 (ANK1) gene was 1115 hypermethylated in AD brains and the methylation was regionally 1116 correlated with the degree of pathology (Lunnon et al., 2014). This 1117 was a novel, replicated observation, which had not been observed 1118 earlier, although on the contrary, these studies could not confirm 1119 many other screening results. To conclude, it seems that more 1120 genome-wide DNA methylation studies will be required to 1121 replicate the results of these initial large-scale and gene-specific 1122 studies. 1123 In addition to DNA methylation, the epigenetic regulation of the 1124 chromatin landscape involves also histone modifications, e.g. 1125 acetylation, phosphorylation, methylation, and noncoding RNA 1126 regulation. Early studies on the chromatin structure indicated that 1127 AD was associated with significant changes in chromatin 1128 organization (Crapper et al., 1979; Lewis et al., 1981; Lukiw and 1129 Crapper McLachlan, 1990; Payao et al., 1998). For instance, the 1130 DNA damage and fragmentation, observed in AD brains (Stadel- 1131 mann et al., 1998; Adamec et al., 1999), affected chromatin 1132 configuration and the presence of heterochromatin (Ball and 1133 Yokomori, 2011). The methylation of histones H3K9 and H3K27 are 1134 the crucial sites for the heterochromatin formation, which is a 1135 repressive modification for gene expression but it has a 1136 fundamental role in the maintenance of nuclear 3D structures. 1137 Recently, Frost et al. (2014) demonstrated that there was a 1138 substantial depletion of H3K9me2 sites in the isolated neuronal 1139 nuclei of post-mortem AD samples. Moreover, the histochemical 1140 staining was more diffuse in AD brains compared to its localization 1141 in perinucleolar chromocenters in age-matched controls. All these 1142 observations indicate that there was likely to be a significant loss of 1143 important heterochromatin structures in AD. In order to verify the 1144 loss of functional heterochromatin, they assayed the expression of 1145 genes which are normally silenced by heterochromatin. Interest- 1146 ingly, they observed that over one third of genes, usually 1147 heterochromatically silenced, were activated in AD samples. It is 1148 known that H3K9me2 is demethylated by KDM3, KDM4, and 1149 KDM7, which are 2-OGDO enzymes and thus controlled by Krebs 1150 cycle intermediates (Salminen et al., 2014b) (Section 4.2). 1151 Frost et al. (2014) also revealed that oxidative stress and DNA- 1152 damage provoked the accumulation of tau protein into the nuclei, 1153 which consequently induced the heterochromatin relaxation. 1154 Oxidative stress is a potent regulator of aberrant DNA methylation 1155 in AD brains (Fleming et al., 2012). There are observations that the 1156 nuclear localization of tau protein enhanced the maintenance of 1157 nucleolar organization (Sjo¨berg et al., 2006). Nizzari et al. (2012) Q31158 demonstrated that there was a reduction in the level of nuclear 1159 phospho-tau in AD patients, simultaneously with the accumula- 1160 tion of phosphorylated tau into neurofibrillary tangles. This 1161 imbalance could disturb heterochromatin maintenance and induce 1162 the instability in ribosomal DNA locus (Hallgren et al., 2014). 1163 Interestingly, Pietrzak et al. (2011) reported that nucleolar 1164 ribosomal DNA was hypermethylated and its content was 1165 increased in cerebrocortical samples from both mild cognitive 1166 impairment (MCI) and AD patients. Future studies will be required 1167 to elucidate the role of epigenetic maintenance of nucleolar 1168 heterochromatin in AD. However, it is known that nucleolar stress 1169


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and disturbances in the epigenetic regulation of ribosomal DNA are involved in Huntington’s disease (Lee et al., 2014b). Interestingly, Murayama et al. (2008) revealed that SIRT1 could NAD+dependently induce histone H3 deacetylation and stimulate H3K9me2 methylation in the ribosomal DNA locus, which consequently inhibited ribosomal RNA transcription. This indicates that NAD+ is a crucial factor in the regulation of energyconsuming ribosome biosynthesis. There is a substantial literature indicating that epigenetic mechanisms regulate learning and memory formation and cognitive disorders with aging (Stilling and Fischer, 2011; Gra¨ff and Tsai, 2013; Zovkic et al., 2013; Fischer, 2014; Guan et al., 2014). Several studies have revealed that memory formation is associated with increased histone acetylation in the hippocampus (Levenson et al., 2004; Peleg et al., 2010; Gra¨ff and Tsai, 2013). In particular, a decrease in histone acetylation seems to have a crucial role in memory impairment in AD. Zhang et al. (2012) used a targeted proteomics to demonstrate that the levels of histone acetylation of H3K18 and H3K23 sites were significantly lower in the temporal lobes of AD patients than age-matched controls. Many experiments have revealed that HDAC inhibitors can ameliorate cognitive defects in transgenic AD mice, e.g. sodium butyrate (Govindarajan et al., 2011), phenylbutyrate (Ricobaraza et al., 2009), trichostatin (Francis et al., 2009), and valproic acid (Kilgore et al., 2010). Interestingly, Guan et al. (2009) demonstrated that the overexpression of neuronal HDAC2 reduced dendritic spine density and synaptic plasticity and inhibited memory formation, whereas the depletion of HDAC2 increased the number of synapses and facilitated memory construction. Gra¨ff et al. (2012) reported that amyloid-b oligomers significantly increased the transcription of HDAC2 gene in cultured mouse hippocampal neurons. Moreover, the expression of HDAC2 was increased in hippocampal CA1 area and the entorhinal cortex of AD patients compared to age-matched controls, whereas those of HDAC1 and HDAC3 were not affected. They also revealed that the transcription of many target genes of HDAC2 was repressed. Recently, Bie et al. (2014) demonstrated that microglial activation induced by amyloid-b fibrils in rat hippocampus triggered the interaction between HDAC2 and methyl-CpG-binding protein 2 (MeCP2). Subsequently, this complex suppressed the acetylation of H3 in neurons and enhanced DNA methylation in the promoter region of neuroligin 1 (NLGN1). The inhibition of NLGN1 expression reduced the numbers of dendritic spines and synapses in the hippocampus. Moreover, they reported that the expression of HDAC2 and MeCP2 was increased and that of NLGN1 decreased in the hippocampus of transgenic AD mice. These studies indicate that HDAC2 expression has a fundamental role in synaptic plasticity and memory consolidation. In addition to the translational changes in the levels of HDAC2 protein, several post-translational modifications, e.g. phosphorylation, nitrosylation, and ubiquitination (Segre and Chiocca, 2011), as well as the metabolites of intermediary metabolism, e.g. acetyl-CoA and NADPH (Vogelauer et al., 2012), can control the activity of HDAC2 and histone acetylation. Currently, comparing the DNA methylation data with different results from both transcriptome and proteomic analyses (Twine et al., 2011; Hallock and Thomas, 2012; Liang et al., 2012; Feng et al., 2014), one might speculate that the pathogenesis of AD involves gradual stochastic changes in the epigenome of only distinct vulnerable neurons disturbing their normal transcription and consequently leading to pathological changes. It seems that the upstream pathological processes, e.g. amyloid-b peptide and tau protein accumulation, mitochondrial dysfunctions, and inflammation, induce tissue-specific secondary changes in the chromatin structures, which promote the deterioration of chromatin landscape in AD brains. Moreover, many microRNA genes are epigenetically regulated in the AD brain (Van den Hove et al., 2014), which

complicates the interpretation between DNA methylation profiles and transcriptomes. Many more aspects of epigenetics in AD have recently been reviewed in detail elsewhere (Adwan and Zawia, 2013; Veerappan et al., 2013; Wang et al., 2013).

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6. Potential role of impaired mitochondrial energy metabolism in the epigenetic regulation of AD pathogenesis

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Mitochondrial dysfunction is associated with many neurodegenerative diseases attributable to either the primary mutations in mitochondrial proteins or more frequently, to secondary insults impairing mitochondrial function (Schon and Manfredi, 2003; Correia et al., 2012; Breuer et al., 2013; Chaturvedi and Flint Beal, 2013). Mitochondrial impairment has also been observed in several other age-related and metabolic diseases, e.g. diabetes and cardiovascular diseases (Supale et al., 2012; Dromparis and Michelakis, 2013). Many common insults can jeopardize mitochondrial function, e.g. oxidative stress and disturbances in calcium balance which impair mitochondrial homeostasis and consequently cellular energy metabolism. On the other hand, tissue-specific factors, e.g. the accumulation of amyloid-b and phosphorylated tau protein into neuronal mitochondria, can disturb mitochondrial function and enhance the appearance of AD-specific phenotype (Section 2). Mitochondrial dysfunctions can also influence immune responses, e.g. activate inflammatory reactions and thus enhance the pathogenesis of many diseases (West et al., 2011; Cloonan and Choi, 2012). Moreover, mitochondria are the major cellular stress sensors and they can even trigger apoptotic cell death (Huttemann et al., 2011; Martinou and Youle, 2011). These characteristics imply that mitochondrial disturbances can augment many aspects of AD pathogenesis through distinct processes at different phases. Given that mitochondria are cellular powerhouses, the retrograde signaling mechanisms from mitochondria to nuclei has a key role in the control of gene expression in adaptive responses to maintain energy metabolic homeostasis (Butow and Avadhani, 2004; Liu and Butow, 2006; Ryan and Hoogenraad, 2007). Currently, it has proved difficult to unravel the mitochondrial retrograde mechanisms in mammalian cells, although many transcription factor pathways, e.g. the NF-kB, C/EBP and CREB pathways, have been implicated. Oxidative stress and calcium imbalance are the main activators of retrograde signaling, which consequently targets distinct gene frameworks (Fig. 4). Recently, more attention has been focused on the mitochondrial unfolded protein response (UPRmt), the corresponding system for the endoplasmic reticulum (ER)-induced unfolded protein response (UPRer), as a signaling pathway for mitochondrial stress responses (Pellegrino et al., 2013; Jovaisaite et al., 2014). Zhao et al. (2002) demonstrated that the mitochondrial stress response activated the C/EBPb-CHOP complex, which controls the expression of mitochondrial stress-related genes, e.g. Hsp60 chaperonin. JNK2 and PKR are the signaling kinases, which stimulate the expression of both C/EBPb and CHOP by activating the c-JUN/AP-1 factor (Jovaisaite et al., 2014) (Fig. 4). Interestingly, CHOP protein is an important apoptotic factor associated with the ER-stress-induced neuronal apoptosis (Liu et al., 2013). Evidence is emerging indicating that there is an intimate crosstalk between ER and mitochondria in the regulation of cellular life and death (Bravo et al., 2011; Vannuvel et al., 2013; Rainbolt et al., 2014). A low-level ER stress appears to enhance mitochondrial respiration and probably induces mitohormetic adaptations, whereas an increased level of ER-stress can disturb mitochondrial bioenergetics and trigger apoptosis. It is known that ER stress is involved in the pathogenesis of AD but its role in the appearance of mitochondrial dysfunctions needs to be clarified (Hoozemans et al., 2006; Salminen et al., 2009a).

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Fig. 4. A schematic presentation illustrating the retrograde signaling pathways induced by the AD-associated mitochondrial stress. A low-level mitochondrial stress stimulates the retrograde signaling via c-JUN/AP-1 targeting C/EBPb transcription interactome, which activates target-specific genes inducing mostly adaptive, mitohormetic responses. Hypoxia inhibits PHD enzymes and stabilizes the expression of HIF-1a, which stimulates the expression of over 300 genes, including many KDMs and indirectly influencing many other epigenetic regulators. The mitochondrial intermediates, i.e. citrate, 2-oxoglutarate, succinate and fumarate, control the function of histone acetylation (HATs), DNA methylation (TET1-3), and histone methylation (KDM2-7). It seems that their responses are dependent on the level of mitochondria stress, i.e. at the low level responses are coordinated but increased stress can induce stochastic changes, which are caused by either a loss of intermediates or their excessive presence, ultimately leading to apoptotic cell death.

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The expression of C/EBPb, also termed the CCAAT box binding protein-b, was significantly increased in AD brains (Strohmeyer et al., 2014), as well as in transgenic AD mice (Ramberg et al., 2011). The C/EBP proteins form heterodimers with many transcription factors and this affects the context-dependent outcome of the transactivation process, e.g. increasing inflammation and neuronal damage (Kapadia et al., 2006; Straccia et al., 2011) or enhancing neurogenesis and memory consolidation (Taubenfeld et al., 2001; Cortes-Canteli et al., 2011). The plethora of C/EBPb-induced responses is attributable to its capacity to bind different epigenetic regulators and in that way affect the expression pattern of target genes and subsequently modulate the epigenetic chromatin landscape. For instance, the C/EBPb protein can interact with the SWI/SNF/Mediator (Kowenz-Leutz et al., 2010) and ISWI complexes (Steinberg et al., 2012), both of which are ATPdependent chromatin remodeling complexes. C/EBPb can also transactivate the expression of G9a, a methyltransferase of the H3K9 site, which is a silencer of chromatin function (Li et al., 2013). Moreover, C/EBPb factor can bind to the promoter of methionine adenosyltransferase 1A (MAT1A) gene and increase its expression (Ikeda et al., 2008). The MAT1A enzyme catalyzes the synthesis of S-adenosylmethionine, which is a methyl donor in the methylation reactions and thus it has a fundamental role in epigenetic regulation. Given that mitochondrial stress in AD brains induces the expression of C/EBPb, it is likely that C/EBPb can trigger not only mitohormetic adaptations but also induce pathological changes, e.g. immune responses (Tsutsui et al., 2013) and cellular proliferation and senescence (Jin et al., 2010; Huggins et al., 2013) via its interactions with epigenetic mediators (Fig. 4). The pathogenesis of AD is associated with an impaired cerebral circulation attributable to cerebral amyloid angiopathy (Kalback et al., 2004; Villarreal et al., 2014). The hypoperfusion, especially at the capillary level, provokes a local hypoxia and can even generate

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microinfarcts (Suter et al., 2002; Pluta et al., 2013; De Reuck et al., 2014). In turn, oxygen deficiency disturbs mitochondrial oxidative phosphorylation and impairs the function of Krebs cycle, provoking accumulation of succinate (Section 4.2). There are three prolyl 4-hydroxylases (PHD1-3), which are specific cellular sensors for molecular oxygen deprivation, i.e. under normoxic conditions they hydroxylate hypoxia-inducible factor-1a (HIF-1a) stimulating its proteasomal degradation, whereas hypoxia inactivates PHDs and HIF-1a accumulates in cells (Bracken et al., 2003; Myllyharju, 2013). Interestingly, the PHD1-3 enzymes are members of the 2OGDO family, as are TET1-3 and KDM2-6 (Sections 4.1 and 4.2). In addition to O2 deficiency, PHD1-3 enzymes can be inhibited by Krebs cycle intermediates, i.e. succinate and fumarate, and thus they can stimulate the expression of HIF-1a (Selak et al., 2005; Koivunen et al., 2007; Hewitson et al., 2007). This metaboliteinduced HIF-1a response has been called pseudohypoxia, and the accumulation of succinate, such as occurs in the case of SDH mutations, is an important cancer promoter (Morin et al., 2014). Experimentally, the pseudohypoxic cellular state induced by the treatment with succinate and fumarate can be alleviated by the exposure of cell-permeable 2-oxoglutarate (MacKenzie et al., 2007). There is an extensive literature highlighting that succinate accumulates in tissues during hypoxia/anoxia (Chinopoulos, 2013). This mechanism does have energy metabolic benefits, since the 2-oxoglutarate, produced by either Krebs cycle or GDH from glutamate (Fig. 1), can be converted into succinate through the activity of 2-OGDH and succinate thiokinase (STK), a process of which can generate ATP without a need for oxygen. There is growing evidence that the PHD-HIF-1a signaling has a major role not only in the pathogenesis of AD but also in many other neurodegenerative diseases (Ogunshola and Antoniou, 2009; Correia and Moreira, 2010; Zhang et al., 2011; Karuppagounder and Ratan, 2012). However, there are observations indicating that the role of HIF-1a signaling in neuronal survival could be a doubleedged sword being either protective or detrimental, i.e. the responses are both context- and dose-dependent. Substantial evidence indicates that hypoxia has an important role in the pathogenesis of the late-onset AD (Zhang and Le, 2010). Sun et al. (2006) reported that hypoxia increased the expression and activity of BACE1 and consequently enhanced APP processing and amyloid-b peptide generation in cultured neurons. They also revealed that hypoxic conditions accelerated the pathogenesis in transgenic AD mice by increasing the b-cleavage of APP and the deposition of neuritic plaques. Zhang et al. (2007) demonstrated that the promoter of the BACE1 gene contained a functional hypoxia response element (HRE), a binding site for HIF-1a factor. They also observed that the overexpression of HIF-1a increased the expression of BACE1 in neuronal cells, whereas the downregulation decreased the level of BACE1 protein. Moreover, they reported that a conditional knockout of HIF-1a in mice reduced the protein level of BACE1 in the brain. The HIF-1a factor can induce the expression of over 300 genes and thus adapt cells to hypoxia or succinate-induced pseudohypoxia. Epigenetic studies have revealed that hypoxia can trigger a profound remodeling of chromatin landscape, which in turn affects gene expression profiles, most probably in a dose-dependent manner (Watson et al., 2010; Perez-Perri et al., 2011; Melvin and Rocha, 2012). Expression studies have indicated that most of the epigenetic changes are induced by the PHD-HIF-1a axis. Xia et al. (2009) observed that the transcriptional targets of HIF-1a involved a striking enrichment of 2-OGDO enzymes, e.g. KDMs, in hypoxic liver cells. The hypoxia-induced increase in the expression of histone KDMs has been confirmed in many cell types (Beyer et al., 2008; Pollard et al., 2008; Krieg et al., 2010; Lee et al., 2014a) (Fig. 4). The response seems to be selective concerning mainly the subtypes of KDM3, 4 and 6, which remove the repressive H3K9 and


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H3K27 methylation marks. Studies also revealed that the transactivation of KDMs was mediated by HIF-1a via their promoter HRE sites. Given that the typical function of KDMs is to serve as the co-activators of transactivation process or enhance the elongation of transcription, it seems that increased KDM expression stimulates the efficacy of HIF-1a, probably also in the case of BACE1. The enhanced transactivation capacity of HIF-1a can also have other harmful effects with respect to AD pathogenesis, e.g. stimulating the expression of pro-apoptotic factors and provoking inflammatory responses (Bacon and Harris, 2004; Shay and Celeste Simon, 2012; Singh et al., 2012). Acetyl-CoA is a key component in intermediary metabolism and thus in the maintenance of cellular homeostasis. Deficiencies in mitochondrial metabolism, e.g. in hypoxic conditions and most likely also present in AD, redirect the energy metabolism from the Krebs cycle and oxidative phosphorylation toward the glycolytic pathway (Kim et al., 2006; Semenza, 2007; Goda and Kanai, 2012). This switch reduces the production of ROS but also the levels of Krebs cycle intermediates, e.g. citrate and 2-oxoglutarate, which could be used for synthetic or regulatory purposes. Citrate and acetylcarnitine are important mitochondrial sources for histone acetylation (Section 4.3), and thus their reduced production during Krebs cycle suppression could decrease histone acetylation in AD brains (Section 5). Another source of acetyl-CoA for utilization in histone acetylation, i.e. the transport of pyruvate dehydrogenase components to nuclei (Section 4.3), is probably also inefficient in AD, since the activity of pyruvate dehydrogenase is significantly reduced in AD brains (Sorbi et al., 1983; Gibson et al., 1998b; Bubber et al., 2005). In transgenic AD mice (3xTg-AD), the protein level of pyruvate dehydrogenase and the activity of mitochondrial respiration were also decreased, preceding the appearance of AD pathology (Yao et al., 2009). Moreover, HIF-1a activates the expression of pyruvate dehydrogenase kinase 1 (PDK1), which subsequently inactivates pyruvate dehydrogenase and thus inhibits the Krebs cycle and the generation of acetyl-CoA (Kim et al., 2006). The shortage of acetyl-CoA impairs acetylcholine synthesis and thus cholinergic neurons are particularly vulnerable to disturbances in mitochondrial function (Szutowicz et al., 2013). It seems that the deficiency of acetyl-CoA generation in AD also very well correlates with a clear decrease in the level of histone acetylation (Section 5). On the other hand, the expression of HDAC2 is increased in AD, which seems to be linked to the cognitive disorders encountered in AD (Section 5). Given that there is a deprivation of histone acetylation and subsequent impairment in gene expression, novel therapeutic options could involve either the inhibition of HDACs (Gra¨ff and Tsai, 2013; Peixoto and Abel, 2013) or increasing acetyl-CoA production, e.g. via ketogenic diets (Kashiwaya et al., 2013; Newman and Verdin, 2014). The level of DNA and histone methylation can also be regulated e.g. by diet (Hardy and Tollefsbol, 2011) and chromatin modifying drugs (Szyf, 2009; Pachaiyappan and Woster, 2014).

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7. Concluding remarks

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AD is a progressive neuronal disorder, which is characterized by its gradual expansion from a few neurons in the transenthorinal cortex to extensive cortical brain regions (Braak and Braak, 1991; Braak et al., 2006). This pathogenic course is quite different from that of the aging process, although aging is the most powerful risk factor of AD. The brain samples from both AD patients and transgenic AD mice have revealed the presence of prominent mitochondrial degeneration in dystrophic neurites and neurons near the amyloid plaques (Fiala et al., 2007; Xie et al., 2013; Choi et al., 2014). Given that many screening studies on gene expression profiles and DNA methylation patterns have reported inconsistent results in AD (Section 5), it is evident that in such a chronic disease

as AD there are present diverse processes varying from the adaptive mitohormesis to apoptotic cell death (Fig. 4). All these processes affect the epigenetic landscape of chromatin in different ways. Considering the adaptive changes, e.g. responses to lowlevel hypoxia or the chronic accumulation of amyloid-b, mitochondrial metabolites induce distinct 2-OGDO pathways, whereas detrimental insults provoke stochastic rather than coordinated responses to cause the death of damaged neurons. It is known that both hypoxia and apoptosis are associated with pronounced changes in epigenetic landscape of chromatin (Fullgrabe et al., 2010; Watson et al., 2010; Meng et al., 2011; Tsai and Wu, 2014). It is important to combine the metabolomic and epigenomic techniques in order to reveal the mechanisms which control the changes in epigenetic landscape caused by the amyloid-b exposure in mitochondrial energy metabolism. The screening results can be confirmed by using cell-permeable metabolites and transgenic techniques in the experiments with cultured neurons. The changes in the mitochondrial energy metabolites provide a sensitive indicator of cellular homeostasis, which controls the fate of neurons through epigenetic regulation during intrinsic and environmental stresses.

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Acknowledgements

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This article was funded by Academy of Finland, VTR grant Q5 Q4 V16001 of Kuopio University Hospital, Sigrid Juselius Foundation, the Strategic Funding of the University of Eastern Finland (UEFBrain), FP7, Grant Agreement no. 601055, VPH Dementia Research Enabled by IT VPH-DARE@IT, and BIOMARKAPD project in the JPND program. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript.

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3-Methylglutaconic aciduria in a patient with a disturbed mitochondrial energy metabolism.

Mitochondrial energy metabolism and apoptosis regulation in glioblastoma.

HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling.

Epigenetic regulation of open chromatin in pluripotent stem cells.

Epigenetic Mechanisms Involved in Huntington's Disease Pathogenesis.

Epigenetic regulation of peroxiredoxins: Implications in the pathogenesis of cancer.

Regulation of energy metabolism and mitochondrial function in skeletal muscle during lipid overfeeding in healthy men.

Impact of exercise on energy metabolism in anorexia nervosa.

Epigenetic regulation in Parkinson's disease.

Chromatin-Based Epigenetic Regulation of Plant Abiotic Stress Response.

Impact of enteral nutrition on energy metabolism in patients with Crohn's disease.

Cellular energy metabolism and regulation.

Regulation of energy metabolism in Saccharomyces cerevisiae. Relationships between catabolite repression, trehalose synthesis, and mitochondrial development.

Epigenetic regulation of mitochondrial function in neurodegenerative disease: New insights from advances in genomic technologies.

Epigenetic Pathways in Human Disease: The Impact of DNA Methylation on Stress-Related Pathogenesis and Current Challenges in Biomarker Development.

Impaired energy metabolism of lymphocytes in cirrhotics after hepatectomy.

Epigenetic Mechanism in Regulation of Endothelial Function by Disturbed Flow: Induction of DNA Hypermethylation by DNMT1.

Mitochondrial Energy Metabolism and Thyroid Cancers.

Mitochondria: impaired mitochondrial translation in human disease.

Chromatin Landscape of the IRF Genes and Role of the Epigenetic Reader BRD4.

Mitochondrial uncoupling proteins and energy metabolism.

Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation.

Epigenetic regulation of vitamin D metabolism in human lung adenocarcinoma.

Coordinated multisite regulation of cellular energy metabolism.