Astrocytes in Health and Neurodegenerative Disease

Glia in the pathogenesis of neurodegenerative diseases Alexei Verkhratsky*†‡1,2 , Vladimir Parpura§1 , Marcela Pekna¶**1 , Milos Pekny¶**1 and Michael Sofroniew††1 *Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, U.K. †Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain ‡University of Nizhny Novgorod, Nizhny Novgorod 603022, Russia §Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy & Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain Institute, University of Alabama, Birmingham, AL 35294, U.S.A. Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia

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¶Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Gothenburg, Sweden **Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia ††Department of Neurobiology, University of California, Los Angeles, CA 90095, U.S.A.

Abstract Exclusively neuron-centric approaches to neuropathological mechanisms have not resulted in major new breakthroughs in the prevention and therapy of neurodegenerative diseases. In the present paper, we review the role of glia in neurodegeneration in an attempt to identify novel targets that could be used to develop much-needed strategies for the containment and cure of neurodegenerative disorders. We discuss this in the context of glial roles in the homoeostasis and defence of the brain. We consider the mounting evidence supporting a change away from the perception of reactive glial responses merely as secondary detrimental processes that exacerbate the course of neurological disorders, in favour of an emerging contemporary view of glial pathological responses as complex and multistaged defensive processes that also have the potential for dysfunction.

Neuroglia: the homoeostatic arm of the central nervous system Neuroglia, represented by highly heterogeneous population of non-excitable cells of ectodermal/neural (astroglia, oligodendroglia and NG-2 glia) and mesodermal/myeloid (microglia) origin, are the primary homoeostatic and defence elements of the central nervous system (CNS). These neuroglial cells contiguously tile the CNS and are chiefly responsible for homoeostasis of the nervous tissue by executing a wide array of housekeeping functions (for recent reviews and extensive reference lists, see [1–3]). Astrocytes play a unique role in balancing neuroprotection and neurotoxicity by controlling the brain environment, regulating brain development, creating the connectome, adopting stem cell properties and controlling the formation, maintenance and demise of synapses, which is the basis of

Key words: Alzheimer’s disease, amyotrophic lateral sclerosis, glia, Huntington’s disease, neurodegeneration, Parkinson’s disease. Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; BD, Batten disease; CD11b, cluster of differentiation molecule 11 b; CNS, central nervous system; EAAT2, excitatory amino acid transporter 2; GABA, γ -aminobutyric acid; GFAP, glial fibrillary acidic protein; GLT-1, glutamate transporter-1; GS, glutamine synthetase; HD, Huntington’s disease; hSOD1, human SOD1; mhtt, mutant huntingtin protein; MPTP, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine; MSN, medium spiny neuron; Nurr1, nuclear receptor-related protein 1; PC, pyruvate carboxylase; PS1, presenilin 1; SOD1, Cu/Zn-superoxide dismutase. 1 All authors contributed equally to this work. 2

To whom correspondence manchester.ac.uk).

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synaptic plasticity and cognition. Furthermore, astrocytes are fundamental for synaptic transmission; they, by virtue of specific enzymes and plasmalemmal and intracellular transporters, control the homoeostasis of major neurotransmitters, glutamate, γ -aminobutyric acid (GABA) and ATP/adenosine [4–6]. Astroglial cells, in particular, supply neurons with glutamine, which is a precursor for both glutamate and GABA. The glutamine supply is critical for neurotransmission, because neurons are devoid of enzymes for de novo synthesis of glutamate (and hence GABA for which glutamate is a precursor), and inhibition of astroglial glutamate–glutamine shuttle eliminates both GABAergic and glutamatergic synaptic transmission [7,8]. Furthermore, astroglia regulate the emergence and development of blood–brain and cerebrospinal fluid–brain barriers, whereas astrocyte end-feet, which cover 99 % of CNS capillary walls, contribute to regulated transport of various substances through these barriers and are also involved in the regulation of local blood flow [9–11]. Astrocytes not only are central for cellular homoeostasis of the CNS, but also contribute to systemic homoeostasis. They are important elements of central chemoception, circadian rhythm and regulation of sleep [12–14]. Oligodendroglia are responsible for CNS myelination and as such are a fundamental part of the ‘connectome’ [15,16]. Of note, although white matter occupies more than 50 % of the human brain volume, its role in numerous neurological  C The

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pathologies remains vastly underestimated. Reduction in myelination and oligodendroglial performance is observed in physiological aging, although decreased densities and/or myelinating capabilities may represent a fundamental, albeit an unknown, part of pathophysiology of neurological and psychiatric disorders. In parallel, oligodendrocytes participate in complex bidirectional communication with axons. For example, oligodendroglial cells contribute to periaxonal ion and transmitter homoeostasis, provide axonal metabolic support and are capable of rapid dynamic regulation of the action potential propagation [17–19]. The functions of NG2 glia, which are closely related to oligodendroglial cell linage, remain hitherto uncharacterized, although it may be an important element of adult myelination and also represent a part of the CNS homoeostatic system [20–22]. Microglial cells are generally regarded as the site of ‘innate immunity’ of the CNS. Microglial progenitors are direct scions of c-kit-positive erythromyeloid precursors originating from the extra-embryonic yolk sac [23]. These progenitors enter very early the developing CNS; in mice, e.g., the invasion begins at embryonic day 10 [24]. The brain environment exerts profound effect on these myeloid precursors that undergo a remarkable metamorphosis that changes their appearance and physiological properties. The resting, i.e. surveillant, microglia have a very specific morphology with a small cell body equipped with several very thin and long processes constantly moving through the brain parenchyma. These movable processes scan the territorial domain of a single microglial cell being able to screen the full volume of this domain within several hours [25]. Microglial cells also acquire numerous receptors for neurotransmitters and neurohormones; in addition, they conserve, from their myeloid progenitors, ‘immunocompetent’ receptors, such as receptors for chemokines and cytokines or Toll-like receptors [26]. With this set of highly diverse receptors, microglia are arguably the most ‘receptive’ cells in the CNS. Microglial role reaches far beyond the innate immunity responsibilities. Microglial cells, being the earliest glia in development, are involved in embryonic synaptogenesis as well as activity-dependent synapse formation in adulthood [27], and they are fundamental for developmental shaping of neuronal networks through synaptic pruning or phagocytosis of redundant or apoptotic neurons [28,29].

Neuroglia: the defensive arm of the CNS The homoeostatic importance of glia is directly linked to its defensive capabilities. Neuroglia in essence form the main and the only system of the CNS defence realized by a complex of cell-specific mechanisms that allow contextspecific responses to a wide variety of environmental challenges. The homoeostatic glial systems are an integral part of this defensive response [3,30], because any type of pathology strains the tissue homoeostasis. Glial homoeostatic systems exert primary neuroprotection by, e.g., containing excitotoxicity (through glutamate and K + buffering), oxidative damage [by secreting the reactive oxygen species  C The

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(ROS) scavengers glutathione or ascorbic acid] or metabolic substrate deprivation (by supplying stressed neurons with lactate). In addition to these housekeeping mechanisms, neuroglia contribute to CNS defence through specific evolutionarily conserved reactions known as reactive gliosis, which is represented by reactive astrogliosis, proliferative response of NG2 cells and activation of microglia [26,31– 37]. Reactive gliosis is (despite the popular view of being solely a pathological and destructive process) a complex, multicellular and multistage defensive response of the nervous tissue aimed at neuroprotection and regeneration; reactive glia are fundamental for containing the damage (through, e.g., the formation of the glial scar), for removing pathogens, dying cells and cellular debris and for remodelling and repairing the nervous tissue after the resolution of pathology [31,35,36]. The astroglial defensive response, defined as reactive astrogliosis, is manifested by a series of co-ordinated biosynthetic processes involving changes in the expression of thousands of genes, which result in the appearance of multiple reactive phenotypes specific to a particular pathology [31,35]. Traditionally, astroglial hypertrophy, astroglial proliferation and up-regulation of the expression of cytoskeletal proteins such as glial fibrillary acidic protein (GFAP), vimentin and/or nestin are considered to be the hallmarks of astroglial reactive response [37,38]. Inhibition of reactive astrogliosis generally reduces neuronal viability, affects nervous tissue regeneration, suppresses neurogenesis and compounds the neurological output [31,39]. Glial response also involves the NG2 glia that react to CNS pathology by an increased proliferation and morphological changes. On a morphological level, the NG2 cellular processes become shorter and thicker; this is accompanied by an up-regulation of chondroitin sulfate proteoglycan [4] synthesis and may initiate proliferation. Reactive NG2 cells were reported to generate oligodendrocytes that are most likely to be fundamental for remyelination of damaged axons [40,41]. The innate immune response of the CNS is provided by microglia, which react to the pathological insults by launching a programme of activation [33,42]. This programme, similar to astroglial reaction, is a multistage and tightly controlled process that progresses through different stages and results in the appearance of multiple ‘activated’ cellular phenotypes. In the course of activation, microglial cells alter the expression of various enzymes and receptors and begin to secrete immune response agents, or else microglia become proliferative and motile, acquire macrophage-like morphology, migrate to and accumulate around the sites of damage and, at the extreme end of activation programme, transform into phagocytes [26,42,43].

The wide spectrum of astrogliopathology: from atrophy and functional asthenia to reactive gliosis Glia are essential for normal brain function and hence their dysfunction and the consequent loss of homoeostasis is a component of the pathogenesis of most, and probably

Astrocytes in Health and Neurodegenerative Disease

all, neurological diseases. To a great extent, the pathogenic changes in glia determine the outcome and scale of neurological diseases. Astroglial contribution to pathology is represented by (i) reactive gliosis, and (ii) acute or chronic astrocytopathology associated with a loss or alteration of their essential functions. Morphological atrophy or functional asthenia of astrocytes has been described for many neurological conditions. Toxic damage to CNS, associated, e.g., with hyperammonaemia, poisoning with heavy metals or Wernicke encephalopathy has, as a primary pathogenetic step, a decrease in astroglial glutamate uptake which triggers massive excitotoxicity and neuronal damage and loss [44,45]. Signs of morphological and functional atrophy occur at the early stages of several neurodegenerative disorders [46], in neurodevelopmental pathology, including autistic spectrum disorders [47], and in a variety of neuropsychiatric diseases [48].

Astroglia in major neurodegenerative diseases Neurodegenerative disorders represent the failure of metabolic and signalling homoeostasis in the brain, which are the recognized functions of glia. For a long time, neurodegenerative diseases have been examined solely from the perspective of neuronal death. Only recently have studies on the pathological potential of glia begun to overturn these ‘neuron-centric’ views. We now know that glial degenerative changes lie at the very core of pathological progression of neurodegeneration, including Alzheimer’s disease (AD) and Parkinson’s disease, white matter diseases and some autistic syndromes. In this section, we provide an overview of the contribution of astrocytes to several major forms of neurodegenerative disorders.

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease in the U.K. and (mainly in the U.S.A.) as ‘Lou Gehrig’s disease’, after the baseball player who suffered and died from this pathology, was described by Jean-Martin Charcot in the 19th Century [49,50]. At the very core of ALS lies a specific degeneration of motor neurons located in the cortex, brain stem and spinal cord, which defines clinical symptoms represented by progressive paralysis and muscle atrophy, which results in respiratory failure causing death [51]. Both familial and sporadic forms of ALS exist, with ∼20 % of familial form associated with dominant mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1). This mutated gene isolated from human material (hSOD1) has been used for generating experimental (in vitro and transgenic animals) models of ALS [52]. Analysis of mechanisms of motor neuron damage performed on various types of these models revealed the primary role of astroglia in this process. It appeared that astrodegeneration and astroglial atrophy associated with the loss of function precede neuronal death and occur before the emergence of clinical symptoms (see [53–55] for further

details and references). In an ALS animal model, in which mutant SOD1 gene was specifically expressed in astrocytes, these cells showed increased vulnerability to extracellular glutamate and were shown to promote activation of microglia and secrete several neurotoxic factors. When expression of mutant hSOD1 gene was silenced in astrocytes, the progression of experimental ALS was markedly decelerated [56]. Incidentally, in vitro primary astrocytes isolated from post-mortem motor cortex and spinal cord of sporadic ALS cases triggered necroptotic death of motor neurons derived from stem cells [56a]. Another critical pathogenetic factor arguably driving ALS neuropathology is associated with deficient glutamate clearance by astroglia. A severe reduction in astroglial glutamate uptake, which is likely to become central for neurotoxic damage, stems from a substantial down-regulation or even disappearance of the astroglial glutamate excitatory amino acid transporter 2 (EAAT2) [in humans; termed glutamate transporter-1 (GLT-1) in rodents] in the vulnerable brain regions. Experimental genetic deletion of GLT-1 in mice caused profound death of motor neurons, thus replicating ALS [57]. It is also argued that in sporadic ALS in humans, reduction in EAAT2 levels may be caused by aberrant RNA splicing, exon skipping and intron retention [53]. Aberrant expression of glutamate transporters in familiar ALS can reflect oxidative damage associated with a malfunction of SOD1. Apart from deficient glutamate uptake, astroglial cells may contribute to neuronal damage by glutamate release. Patients with ALS are reported to have increased levels of cyclooxygenase [2], which in turn produces prostaglandin E2 , a potent activator of glutamate release from astrocytes [53]. At the later stages of ALS, reactive astrogliosis also comes to the fore, as well as the activation of microglial cells [53,58]. Microglial activation was detected in the mice overexpressing mutant SOD1, where this process appeared before the emergence of neuronal lesions and disease symptoms. Selective silencing of the mutated SOD1 gene in microglia, transplanting wild-type bone marrow cells, or treatment with anti-inflammatory drugs increased the animal survival rate and delayed the disease progression [59–61]. To conclude, both astrocytes and microglia may well appear as central players in the ALS pathology. At the initial stages of the disease, astroglial cells suffer atrophy and functional weakness, which, in turn, affect glutamate homoeostasis and induce glutamate excitotoxicity; at the later stages, reactive response of astrocytes and microglia may further exacerbate neuronal damage and ultimately mediate their death.

Alzheimer’s disease Astroglial involvement in AD pathology, similar to other neurodegenerative processes, is represented by a combination of astroglial atrophy (which begins at the early stages of the disease) and reactive astrogliosis with reactive astrocytes mainly concentrating around senile plaques. Evidence favouring the involvement of early degenerative changes in astroglia in AD progression was obtained from recent studies on transgenic AD mouse models [62–70].  C The

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√ √ Figure 1 Decreased GFAP surface (S), volume (V), 2 S/3 V ratio and body volume in both the DG (A, C and I) and the CA1 (B, D and J) of the hippocampus of the 3×Tg-AD mice when compared with control animals (A–D, I and J), and confocal micrographs of astrocytic atrophy (E–H) Results are means ± S.E.M. *P < 0.05. Confocal micrographs illustrating the astrocytic atrophy in 3×Tg-AD mice in the DG (F) and CA1 (H) compared with control animals (E and G respectively). Modified from [64] with permission: Olabarria, M., Noristani, H.N., Verkhratsky, A. and Rodr´ıguez, J.J. (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic c 2010 Wiley-Liss, Inc. animal model of Alzheimer’s disease. Glia 58, 831–838. 

Atrophic astrocytes, i.e. a decrease in astroglial complexity seen as reduced volume of cell somata and decreased number of primary processes in GFAP-positive and glutamine synthetase (GS)-positive cells (Figure 1), were found in several brain regions of 3×Tg-AD mice {harbouring mutated genes for presenilin 1 (PS1), amyloid precursor protein (APP) and tau [71]} as well as in hippocampus of PDAPP-J20 mice expressing a mutant version of APP, a model of amyloidosis [62]. The emergence of atrophic astroglia varied between brain regions [63–65,69] from being evident very early (at 1 month of age) in the entorhinal cortex, to somewhat later  C The

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in the prefronatal cortex (∼ 6 months) and substantially later in the hippocampus (∼9–12 months). In all regions, however, the appearance of atrophic astroglial cells preceded β-amyloid deposition and formation of senile plaques. Astroglial atrophy can be an important part of early pathogenesis of AD. First, atrophic astrocytes reduce synaptic coverage that may seriously affect synaptic transmission and neurotransmitter homoeostasis [46]. Secondly, degenerated astroglial cells affect neurovascular connections. It is generally appreciated that AD pathology is almost invariably associated with vascular deficiency [72,73].

Astrocytes in Health and Neurodegenerative Disease

Astroglial atrophy may seriously affect the glio-vascular unit and contribute to the vascular component of the AD. Thirdly, asthenic astroglial cells may impair neuronal metabolic support, which indeed is generally observed in AD [74]. All these changes are likely to weaken synaptic transmission and affect synaptic plasticity, and are thereby responsible for the initial cognitive deficiency observed at early stages of AD. Reactive astrocytes accumulated around amyloid plaques are a well-known histopathological feature of the AD and in the past were often considered a component of the neurotoxic neuroinflammatory response [75,76]. Sporadically, in brain slices from a mouse AD model, astrocytes were also shown to degrade amyloid plaques [77], for which activity was demonstrated to depend on apolipoprotein E [78]. Astroglial reactivity, however, may vary between different brain regions affected by the AD-type pathology. For example, in the 3×Tg mice, astrogliotic response is initiated in response to emergence of senile plaques and perivascular βamyloid deposition [64,65]. In the entorhinal and prefrontal cortices, however, astrogliotic response is compromised and extracellular accumulation of β-amyloid fails to activate astrocytes [63,69]. These deficits in astroglial reactivity may underline the high vulnerability of entorhinal and prefrontal cortices to AD pathology. Genetic deletion of the astrocyte intermediate filament proteins GFAP and vimentin (which are structural components of the cytoskeleton and form a signalling platform [79,80]) in mice (GFAP − / − Vim − / − ), diminishes reactive gliosis [81,82] and decreases CNS resistance to various insults such as severe mechanical stress [83,84] and ischaemic stroke [85]. At the same time, GFAP − / − Vim − / − mice showed improved regeneration after brain [86] or spinal cord trauma [87], and increased hippocampal neurogenesis in the adulthood [88], in old age [89] or after neurotrauma [88]. Better integration of retinal grafts was also observed in these animals [90], as well as neuronal and astrocyte differentiation from donor neural stem cells transplanted in the hippocampus [91]. When an AD mouse model (APPswe/PS1E9 transgenic mice) was crossed with GFAP − / − Vim − / − mice, the resulting APP/PS1GFAP − / − Vim − / − mice had an increased amyloid plaque load and more prominent neurite dystrophy compared with APP/PS1 AD mice [92] (Figure 2). Neither expression nor processing of APP was affected, suggesting that reactive astrocytes affect plaque growth dynamics by interacting with these plaques directly, rather than via interference with amyloid protein synthesis or metabolism. Therefore it seems that in AD, reactive astrocytes inhibit the amyloid plaque formation/growth through a process that requires physical contact between plaques and neighbouring astrocytes. It is possible that a release of matrix metalloproteinases by reactive astrocytes around plaques contributes to plaque degradation [92–94]. Increased β-amyloid load and neurite dystrophy seen in AD mice with the GFAP − / − Vim − / − background might be, at least in part, caused by impaired interactions between the brain vascular system and astrocytes. Brain capillaries are covered by end-feet of astrocytes, which are polarized

by pericytes [95], and it is conceivable that the astrocyte– endothelial cell interaction becomes even more critical for homoeostasis under pathological conditions, such as AD, than in a healthy brain. Astrocytes were suggested to be actively involved in the removal of amyloid protein across the blood–brain barrier [94], and it is possible that the β-amyloid clearance into the blood compartment [96] is altered in the AD mice on the GFAP − / − Vim − / − background. It is unclear how reactive astrocytes in AD reduce the extent of neurite dystrophy. Although the increase in neurite dystrophy in GFAP − / − Vim − / − mice could be simply a direct consequence of higher β-amyloid load, a more direct involvement of reactive astrocytes could also be a factor that plays a role in this process. For example, neuroprotective effects of reactive astrocytes are executed by the extracellular control of ion concentration and by neurotransmitter recycling [1], and these functions are even more critical under cell and tissue stress [80]. Therefore fewer processes of astrocytes around the plaques, their less efficient gap junctional communication, reduced glutamate uptake [85], or impaired physical barrier around plaques compared with AD mice with normal astrocyte responses [97], might explain this phenotype. These results showed that attenuation of reactive gliosis by genetic ablation of the astrocyte intermediate filament system facilitated progression of AD, implying that reactive astrocytes in AD play a beneficial role. This conclusion receives support from studies on the role of reactive astrocytes in another neurodegenerative disease, i.e. Batten disease (BD; infantile neuronal ceroid lipofuscinosis) [98–100]. The up-regulation of GFAP is the first pathological sign [101,102] in a BD mouse model {mice deficient in palmitoyl protein thioesterase 1 (PPT1) [103]}. GFAP − / − Vim − / − mice on a BD background showed an earlier disease onset, with accelerated progression and earlier death; neurodegeneration and immune cell infiltration were also more prominent [104]. Results from the above experiments also point to a relationship, possibly bidirectional, between the activation of astrocytes and activation/recruitment of microglia and monocytes in neurodegeneration. Genetic ablation of GFAP and vimentin leads to attenuated cluster of differentiation molecule 11 b (CD11b)-positive microglia/monocyte infiltration after retinal detachment, suggesting that reactive retinal glial cells participate in the recruitment of microglia/monocytes to the site of injury, conceivably through production of chemokines, e.g. monocyte chemoattractant protein1 [105]. When migration of astrocytes and the lesion demarcation by astrocytes in the injured spinal cord were inhibited by reactive astrocyte-specific signal transducer and activator of transcription 3 (STAT3) ablation, the CD11b-positive microglia/monocyte infiltration increased, the lesion area became larger and the functional impairment was more pronounced [106–108]. Attenuation of reactive gliosis by GFAP and vimentin ablation in AD mice led to a higher abundance of microglial cells around plaques (Figure 2E) and to increased cortical expression of CD11b and ionized calcium-binding adapter molecule 1 (Iba-1), markers  C The

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Figure 2 AD mice crossed with mice deficient for intermediate filament proteins GFAP and vimentin with attenuated reactive gliosis (GFAP − / − Vim − / − ) show more pronounced amyloid plaque deposits and more prominent microglial infiltration of the plaques (A) Cerebral cortex and hippocampus of 4-, 8- and 12-month-old AD and AD/GFAP − / − Vim − / − mice. Amyloid plaques were visualized with antibodies against β-amyloid. (B and C) Astrocytes (in green) in 12-month-old mice visualized by an injection of associated adenoviral construct driving the expression of GFP in GFAP-expressing astrocytes, and examined 1 month later. Amyloid plaques were labelled with X-34 (blue). In AD mice, processes of reactive astrocytes are in intimate contact with amyloid plaques and show signs of hypertrophy. In contrast, in AD/ GFAP − / − Vim − / − mice, no hypertrophy of astrocyte processes is seen and physical interactions between astrocytes and amyloid plaques are very limited. Results are means ± S.E.M.; n = 58–61 plaques in three mice/group. ****P < 0.0001. Scale bar, 50 μm. (D and E) Higher density of microglia (visualized by antibodies against Iba-1, green) in the vicinity of amyloid plaques (blue) of 8-month-old mice, with more prominent infiltration of the amyloid plaques in AD/GFAP − / − Vim − / − mice compared with AD mice. Results are means ± S.E.M.; n = 3 mice/group. *P < 0.05, ***P < 0.001. Scale bar, 20 μm. Reproduced from [35] Pekny, M., Wilhelmsson, c 2014, U. and Pekna, M. (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci. Lett. 565C, 30–38.  with permission from Elsevier. (B and D) Originally from [92]: Kraft, A.W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S.C., Brown, J., Wilhelmsson, U., Restivo, J.L. et al. (2013) Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J. 27, 187–198. Modified with permission.

of microglia/monocyte [92]. Similarly, BD mice on the GFAP − / − Vim − / − background showed an increased number of CD68-positive microglia/monocytes in the brain [104]. Thus activated astrocytes might negatively control the recruitment and activation of microglia [92]. Inflammatory cytokines and chemokines such as tumour necrosis factor-α and interferon-γ were strongly increased in BD brains, but not in AD brains with attenuated reactive gliosis [92,104], supporting the notion that the role of various neuroinflammatory processes in neurodegeneration is contextdependent. Genomic analysis of reactive astrocytes isolated from the different injury models, namely ischaemic stroke and lipopolysaccharide (LPS)-induced neuroinflammation,  C The

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supports the concept of context-dependent astrogliosis by showing that the reactive astrocyte phenotype is dependent on the type of inducing injury [109].

Huntington’s disease Huntington’s disease (HD) is an autosomal dominant and progressive neurodegenerative disorder. It is caused by the triplet repeat cytosine-adenosine-guanine (CAG), encoding glutamine, in exon 1 of the widely expressed huntingtin gene [110]. The expression of the affected allele results in the synthesis of mutant huntingtin protein (mhtt) containing an expanded polyglutamine section in its N-terminal portion [110,111]. The carrier of an allele with the CAG repeat

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expansion lengthier than 40 will develop HD in the midforties [110–112]; the age of disease onset is inversely correlated to the length of the CAG repeat expansion [111,113]. The carriers with shorter CAG repeat lengths (36– 40) may develop HD symptoms at a very old age [114–116]. At the cellular level, neurodegeneration that occurs in HD is most evident in striatal medium spiny neurons (MSNs) and to a smaller degree in cortical pyramidal neurons [117,118]. However, the expression of mhtt in neurons alone cannot recapitulate key features of HD [119,120]. Indeed, mhtt is present in astrocytes [121], whose function is also altered in HD [122,123]. For example, in the R6/2 HD mouse model containing 144 CAG repeats [124], there is a defective astrocytic glutamate uptake [125,126], associated with the reduction in the mRNA and protein levels of GLT-1 (rodent)/EAAT2 (human) [125]. This can lead to increases in striatal extracellular glutamate levels [127,128] and neuronal vulnerability to toxicity [129]. These findings are consistent with astrocytes being the main site of glutamate uptake, the impairment of which can contribute to glutamate excitotoxicity [130]. An additional disorderly component of HD astrocytes in their homoeostatic regulation of extracellular glutamate levels is via an enhanced Ca2 + -dependent vesicular exocytosis of this transmitter, as has been demonstrated in a different model of HD [131]. This BACHD mouse model contains full-length human mhtt with 97 polyglutamine residues encoded by a modified huntingtin transgene on a human bacterial artificial chromosome (BAC) [132,133]; mhtt is expressed throughout the brain of the BACHD mice in astrocytes and neurons alike. Cultured cortical BACHD astrocytes showed enhanced Ca2 + -dependent exocytotic release of glutamate, which could not be explained by unaltered Ca2 + dynamics, but was rather due to increased expression of pyruvate carboxylase (PC), the critical enzyme for glutamate de novo synthesis. This leads to an increased availability of cytosolic glutamate for vesicular packaging and, consequently, augmented gliotransmission (Figure 3). Another well-known astrocytic homoeostatic function is to regulate extracellular potassium. Recently published work indicates that this function can be affected in two models of HD [134], the already mentioned R6/2 and also the Q175 model, which carries ∼188 CAG repeats [135]. Astrocytes with mhtt nuclear inclusions had decreased expression of Kir 4.1 K + channels, which are chiefly responsible for K + siphoning/buffering. This was associated with increases in striatal extracellular K + levels in vivo and in MSN excitability in vitro. Molecular genetic manipulations to restore functional levels of Kir 4.1 channels in striatal astrocytes returned extracellular K + and MSN excitability to normal, along with improvement of some (but not other) motor functions in R6/2 mice. Taken together, the astrocytic regulation of glutamate and potassium extracellular levels contributes to pathology seen in HD and the identified molecular entities, i.e. EAAT2, PC and Kir 4.1 channels, may represent a fertile ground for novel therapeutic interventions in this devastating disease.

Figure 3 Regulation of glutamate in Ca2 + -dependent exocytotic glutamate release from astrocytes Glucose is broken down to pyruvate in the cytosol. Glutamate (Glut) can be synthesized in astrocytes de novo due to pyruvate entry to the tricarboxylic acid cycle via PC, and downstream transamination of α-ketoglutarate (α-KG) via mitochondrial aspartate aminotransferase (AAT). Once in the cytosol, the synthesized glutamate can be converted into glutamine (Gln) by GS, or transported into vesicles via vesicular glutamate transporters (VGLUTs). In BACHD astrocytes, there is an increased expression of PC.

Parkinson’s disease The role of astrocytes in Parkinson’s disease and related syndromes is not well understood [136]. In autopsy specimens of substantia nigra from idiopathic Parkinson’s disease patients, reactive astrogliosis is generally mild or moderate and is rarely severe [137,138]. Astrogliosis with GFAP up-regulation is noted in 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-associated parkinsonism [139]. Astrocytes have been implicated as potentially exerting both neurotoxic and neuroprotective activities in Parkinson’s disease and its experimental models [140]. Astrocytes take up MPTP from the bloodstream and convert it into neurotoxic 1methyl-4-phenylpyridinium (MPP + ), giving rise to the idea that astrocytes may similarly convert other environmental molecules that have been implicated in dopaminergic toxicity [141,142]. Nevertheless, various findings suggest neuroprotective roles for astrocytes in Parkinson’s and related conditions. For example, activation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) selectively in astrocytes protects mice from MPTP-induced parkinsonism by activating antioxidative response pathways [143]. In addition, a rare form of familial Parkinson’s disease is caused by mutations in nuclear receptor-related protein 1 (Nurr1), and it has been shown that expression  C The

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of Nurr1 in astrocytes suppresses production of potentially toxic molecules and protects against loss of dopaminergic neurons [144]. Recent findings also show that subpopulations of astrocytes express disease-related proteins such as αsynuclein, parkin and phospho-tau to different levels and in different combinations in Parkinson’s disease, multiplesystem atrophy and progressive supranuclear palsy [145], but the roles of astrocytes in these conditions are not yet defined.

Conclusions: challenges and therapeutic potential The neuron-centric pathological doctrine, hitherto, has not resulted in major new breakthroughs in the prevention and therapy of neurodegenerative diseases. By identifying the pathogenic potential of glia, we can develop strategies for the containment and cure of neurodegenerative disorders. However, the pathophysiology of glia is ill-defined and glial responses to pathology are too often considered merely as secondary detrimental processes that exacerbate the course of neurological disorders. This oversimplified view is far from the true nature of the involvement of glia in pathological responses, which are complex, multistaged and defensive.

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Funding This research is supported by the Alzheimer’s Research Trust (UK) Programme Grant [grant number ART/PG2004A/1] to A.V.; by the National Institutes of Health (The Eunice Kennedy Shriver National Institute of Child Health and Human Development award [grant number HD078678] to V.P.; by the Swedish Medical Research Council [grant number 20116] and the ALF Gothenburg [grant number 42821] to M. Pekna, by the Swedish Medical Research Council [grant number 11548], the ALF Gothenburg [grant number 11267] to M. Pekna, the Sten A. Olsson Foundation for Research and Culture, Hjarnfonden, ¨ Hagstromer’s ¨ Foundation Millennium, E. Jacobson’s Donation Fund, NanoNet COST Action [grant number BM1002] and the European Union Framework Programme 7 project TargetBraIn [grant number 279017] to M. Pekny and by the European Union Framework Programme 7 project EduGlia [grant number 237956] to A.V. and M. Pekny.

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Received 29 April 2014 doi:10.1042/BST20140107  C The

C 2014 Biochemical Society Authors Journal compilation 

1301

Glia in the pathogenesis of neurodegenerative diseases.

Exclusively neuron-centric approaches to neuropathological mechanisms have not resulted in major new breakthroughs in the prevention and therapy of ne...
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