1. Please check and comment entries here.
Table of Contents

    Topic review

    Astrocytes Involvement in AD

    Subjects: Others
    View times: 34

    Definition

    Astrocytes, the most numerous glia cells in the brain, have many housekeeping functions, maintain the homeostasis of the CNS and are responsible for neuroprotection and defense. Long regarded as a non-specific, mere consequence of AD pathology, activation of astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their interplay with microglia and neurons can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely relevant in healthy conditions and disease processes. Understanding the spatial differences and roles of glia will allow assessing how those interactions can influence the state and progression of the disease, and will be critical to identify therapeutic strategies.

     

    1. Introduction

    In the healthy brain, astrocytes regulate the formation, maturation, and plasticity of synapses [1][2], are indispensable for neurotransmitter homeostasis [3][4], and control the formation of neural circuits [5][6][7][8][9]. Astrocytes release gliotransmitters [10][11][12][13] necessary for synaptic plasticity [12][14], and control GABA and glutamate extracellular levels at the synapses. Astrocytes mediate the synaptic functions [15][16] and are thus involved in memory formation [12][13][14][17][18]. Healthy astrocytes are fundamental cells of the neurovascular unit, and help maintaining the integrity and the functionality of the BBB and of the glymphatic system [19][15][20][21][22]. It has been proposed that vascular dysregulation and breakdown of the BBB may be one of the first steps in AD pathogenesis [23][24], affecting Aβ clearance [25]. Furthermore, the glymphatic system facilitates the clearance of interstitial solutes including Aβ and tau [26]. Astrogliosis causes loss of AQP4 polarization in perivascular astrocytes, which may represent a mechanism common to neurovascular unit (NVU) and glymphatic dysfunctions in many neurodegenerative diseases such as AD [27][28]. It has been shown that the glymphatic function is disrupted around microinfarcts, especially in the aging brain [26]. All these data taken together may suggest that microlesions of the neurovascular unit, also disrupting the glymphatic system, may trap proteins within the brain parenchyma, increasing the risk of amyloid plaque formation [26].

    2. Astrocytes in pathological mechanisms

    Yet, the understanding of the multiple, contrasting roles of astrocytes in pathological mechanisms entered into focus only very recently. Pathological phenotypes of astrocytes are responsible for three major responses to insults: (i) reactive astrogliosis, (ii) astroglial atrophy and loss of function and (iii) pathological remodeling [29][30].

    In AD patients and in amyloid-mouse models of AD [31][32][33][34], astrocytes have high levels of GABA. In two different mouse models of AD, APP/PS1 mice (APP KM670/671NL (Swedish), PSEN1 L166P) [32] and 5xFAD mice (APPSwFlLon, PSEN1*M146L*L286V) mice [34], tonic release of GABA from hypertrophic astrocytes [32][33][34] located in the vicinity of Aβ plaques was demonstrated. At first, release of GABA from astrocytes, activating GABAA and GABAB receptors, causes a decrease in glutamate release, with a consequent decrease in excitotoxicity and neuroinflammation [35]. Later, the excess of GABA can unbalance the subtle inhibitory–excitatory equilibrium in the neuronal network, inducing inhibition of synaptic plasticity [33]. It has also been shown that astrocytes degeneration may cause the downregulation of glutamate transporters. The two most expressed isoforms of glutamate transporters in the hippocampus are EAAT-1 (Excitatory amino acid transporter-1, GLAST in rodents), and EAAT-2 (Excitatory amino acid transporter-2, GLT1) [36], mainly expressed on astrocytes. Decreased expression of either one or both glutamate transporters compromises the ability of astrocytes to reuptake the excess of glutamate, and to regulate glutamatergic transmission. This in turn results in severe excitotoxicity that underlies rapid development of severe dementia, as shown in Wernicke encephalopathy [37][38]. In AD pathogenesis the situation seems still controversial. In AD patients, the Aβ peptide has been shown to downregulate the functional activity of glutamate transporters [39]. However, in a subsequent study, the Aβ peptide was reported to increase the cell surface expression of GLAST and augment the glutamate clearance ability of cultured astrocytes [40]. Nevertheless, it has been reported that impairment of glutamate uptake is involved in the pathogenesis of AD and other neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, and epilepsy (reviewed in detail elsewhere [41][42]).

    3. Astrocytes in AD

    In AD, in different brain regions and subregions, astrocytic modifications are highly heterogeneous and can result in either hypertrophy or atrophy [43][44][45][46]. In a triple transgenic mouse model of AD, Aβ plaques trigger astrogliosis, which is, however, different among brain regions. Indeed, Aβ causes hypertrophy of astrocytes mainly in the CA1 region of the hippocampus [43][47] while in the entorhinal and prefrontal cortex it causes little sign of astrogliosis [48][49]. Furthermore, in the hippocampus hypertrophic astrocytes are located in close proximity to Aβ plaques, both in animal models [47] and in post mortem brain tissue from AD patients [50][51], a strategic location that is considered neuroprotective. Indeed, it has been demonstrated with PET (Positron Emission Tomography) scan in human patients that the decrease in astroglial reactivity parallels the switch from mild cognitive impairment to AD, again demonstrating the neuroprotective role of astrogliosis, at least in the prodromal phases of AD [46]. More distantly from the plaques, astrocytes look atrophic [47].

    Recent studies have demonstrated that different CNS injuries stimulate at least two types of astrocytes with strikingly different properties, A1 reactive astrocytes, with detrimental properties for neurons, and A2 reactive astrocytes with beneficial, neuroprotective properties. Indeed, A2 reactive astrocytes release neurotrophic factors and cytokines that promote neuronal survival and neurogenesis, as well as synaptogenesis and repair of the damaged synapses. Among the neurotrophic factors or cytokines released by A2 astrocytes are BDNF, IL-6, CLCF1, GDF15, and thrombospondins. In addition, A2 astrocytes release gliotransmitters such as glutamate, GABA, ATP, and neuromodulators such as kynurenic acid and d-serine [52][53]. In the presence of high levels of proinflammatory cytokines, activated astrocytes increase ROS and NO production through induction of the NF-κB pathway [54]. A1 neuroinflammatory astrocytes upregulate many genes that express proinflammatory proteins and other neurodegenerative substances [52]. Recently it has been demonstrated that astrocytes in their A1 state release factors that are toxic to neurons and oligodendrocytes, and lose their phagocytic activity and possibly their ability to dispose of Aβ plaques [53]. Suppression of astroglial reactivity and phagocytosis exacerbates Aβ load and reduces neuroprotection [55].

    Although astrocytes so far have been shown to acquire these two distinct reactive states, more recently it has been postulated that they may acquire many possible activated states in both the healthy and diseased brain (also see [56]). These different states depend not only on the type of insult but also on the brain structure in which they are located [52]. Indeed, nine different groups of astrocytes have been defined [57]. This result possibly indicates that astrocytes acquire a reactive phenotype in function of the local microenvironment, even in healthy conditions [57].

    Nevertheless, it is not understood completely yet whether astrocytes located in different cerebral structures respond to the same insult with the same morphofunctional modifications or whether they react differently to the same insult. In other words, whether astrocyte responses to injuries are controlled by intrinsic cues, or whether they depend upon external signals that come from the environment [58][59]. A third hypothesis is that there may exist a continuum in the diversity and intensity of astrocyte reaction, which possibly hides different, discrete reactive states. Recent work has demonstrated that astrocytes located in distinct anatomical regions have different molecular profiles [60][61], suggesting that astrocytes have site-specific functional roles. Astrocytes derived from different CNS regions respond differently to Aβ in vitro [62]. Indeed, this finding indicates that astrocyte heterogeneity is at least partially intrinsic, possibly due to preexisting differences between astrocytes from distinct brain regions [63][60][64][65][66][67][68]. In the mouse, hippocampus specific, age-exacerbated reactive astrogliosis causes higher vulnerability to age-related neurodegeneration [69]. For instance, an age-related morphofunctional modification of astrocytes called clasmatodendrosis, has been found in the rat hippocampus [70][71][72][73][74]. Indeed, in the white matter of patients with cerebrovascular dementia and AD [75], and in patients with mixed dementia [76], astrocytes show clasmatodendrosis, which correlates directly to changes in cell function [77]. Clasmatodendrotic astrocytes have swollen and vacuolized cell bodies, shorter branches, and loss of distal processes that cause less endfeet coverage of brain vessels. These latter modifications can contribute to vascular deficits observed during aging and in AD. Furthermore, since astrocyte endfeet are main components of the BBB, their fragmentation by clasmatodendrosis can contribute to the impairment of the functionality of the barrier. Aβ clearance is essential for neuroprotection against AD, and in mouse models of AD the impairment of Aβ clearance increases neurodegeneration [78]. The deposition of high quantities of fibrillar Aβ modifies the interactions between astrocytes and neurons [71], possibly decreasing Aβ peptide disposal to the circulating system, and consequently, increasing Aβ deposition in brain parenchyma [79] that may play a significant role in neuronal damage. Therefore, clasmatodendrosis can hamper astrocyte-mediated Aβ clearance from neurons and increase fibrillar Aβ deposition [71][80].

    It has been shown that Aβ reacts with receptors located on astrocytes such as CD36 (cluster of differentiation 36), RAGE (receptor for advanced glycation end products), SCARA-1 (scavenger receptor A-1), and MARCO (macrophage scavenger receptor with collagenous structure). RAGE is one of the most characterized scavenger receptors, and binding to Aβ causes proinflammatory modifications in astrocytes [81]. RAGE mediates the phagocytic profile of astrocytes [82] and the interaction with other ligands, including S100β, involved in AD neuroinflammation [83]. SCARA-1 is involved in Aβ clearance [61], while MARCO may decrease the inflammatory response of microglia [84], and CD36 and RAGE are implicated in the scavenging activity of microglia caused by Aβ (for references see [85]). CD36 cooperates with toll like receptors (TLR-6 and TLR-4), causing ROS production and inflammasome activation [86]. We know that expression of many proinflammatory proteins is increased in astrocytes but, interestingly, not only genes that are upregulated but also those that are down regulated may help understand the roles of reactive astrocytes in disease pathogenesis. However, no established list of down-regulated genes across multiple diseases and especially in AD so far exists [87]. To make things even more complicated, in an animal model of AD different proinflammatory proteins are expressed at different levels in astrocytes located in different areas within the hippocampus [43]. Indeed, molecular changes in astrocytes are highly context-specific, with about 50% of modified gene expression that depends on the type of brain damage [88].

    It has been shown that astrocytes can participate with microglia in phagocytic events [89][90][91][92][93]. Astrocytes use the ABCA1 [92], MEGF10, and MERTK [94], as well as BAI1 and integrin αvβ3 or αvβ5 [95] pathways for phagocytosis. Since astrocytes are not as mobile as microglia [96][97], they are not able to migrate, but polarize their distal processes, and engulf apoptotic bodies derived from dendrites of dying neurons or other toxic material such as Aβ. Astrocytes and microglia play orchestrated roles in a highly coordinated way, with differences in different brain areas that can have important physiopathological consequences [92]. Reactive astrocytes have dual roles in Aβ plaque degradation. The phagocytic role of reactive astrocytes in amyloid pathology may contribute to the clearance of dysfunctional synapses or synaptic debris, thereby restoring impaired neural circuits and reducing the inflammatory impact of damaged neurons [98].

    Notwithstanding all this new evidence, the role of astrocytes in AD is still controversial. On one side, astrocytes are able to remove Aβ fibrils from neuron membranes [80] for their disposal [79]. On the contrary, it has been demonstrated that astrocytes may also contribute directly to Aβ peptide overproduction especially in the presence of increased cellular stress caused by environmental factors and increased neuroinflammation [80][99][100][101][102][103]. On the other side, a decrease in the size of astrocytes and reduction in the number of GFAP-positive primary branches is observed in the hippocampus, prefrontal cortex, and entorhinal cortex at the early stages of the pathology in mouse models of AD [47][48][104][105]. These phenotypic modifications can possibly cause decreased Aβ disposal and increased Aβ extracellular levels.

    In the healthy brain, astrocytes are organized in non-overlapping domains while reactive astrocytes lose their domain organization. The significance of astrocytic domains in health and their spatial dysregulation in disease remains unclear. Many chronic neurological disorders are accompanied by chronically stressed, degenerated, and atrophic astrocytes with loss of function, which adds to the progression of the disease. At the early stages of AD, gliosis is markedly increased, and reactive astrocytes are located around Aβ plaques [47][106][107], while large numbers of astrocytes undergo atrophy [108]. In these conditions, astrocytes undertake a series of phenotypic and functional changes [109] that lead to the formation of a sort of scar around the plaque. Scar formation starts as a defensive reaction aimed at the isolation of the plaque from the healthy tissue for neuron survival. To this aim, astrocytes release neuroprotective agents such as BDNF, VEGF, CLCF1, thrombospondins and bFGF, or IL6 and GDF15 [109].

    4. Conclusions

    Whether glial cells adopt phenotypes that aggravate tissue injury or promote brain repair, most likely depends on different sets of factors, such as the nature of the damaging element, the time course of injury, the severity score that determine the precise arrangements of signals deriving from the surrounding environment. Therefore, the response is possibly not univocal but largely depends on the disease context.

    The idea that the same stimulus/injury activates different types of astrocytes cells in different regions of the brain raises many questions. How many reactive astrocytescell types are there?  What are the cell-cell interactions that induce reactive astrocytes? What are the relevant extracellular and intracellular signaling pathways that induce reactive astrocytes? 

    Answering to all these questions will shed light on how those interactions can influence the disease state, the progression of the disease, and will be critical to identify therapeutic strategies for recovery.

    This entry is adapted from 10.3390/ijms21249441

    References

    1. Hakan Kucukdereli; Nicola J. Allen; Anthony T. Lee; Ava Feng; M. Ilcim Ozlu; Laura M. Conatser; Chandrani Chakraborty; Gail Workman; Matthew Weaver; E. Helene Sage; et al. Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proceedings of the National Academy of Sciences 2011, 108, E440-E449, 10.1073/pnas.1104977108.
    2. Karen S. Christopherson; Erik M. Ullian; Caleb C.A. Stokes; Christine E. Mullowney; Johannes W. Hell; Azin Agah; Jack Lawler; Deane F. Mosher; Paul Bornstein; Ben A. Barres; et al. Thrombospondins Are Astrocyte-Secreted Proteins that Promote CNS Synaptogenesis. Cell 2005, 120, 421-433, 10.1016/j.cell.2004.12.020.
    3. Frank W. Pfrieger; Roles of glial cells in synapse development. Cellular and Molecular Life Sciences 2009, 66, 2037-2047, 10.1007/s00018-009-0005-7.
    4. Michael T. Heneka; José J. Rodríguez; Alexei Verkhratsky; Neuroglia in neurodegeneration. Brain Research Reviews 2010, 63, 189-211, 10.1016/j.brainresrev.2009.11.004.
    5. David Stellwagen; Robert C. Malenka; Synaptic scaling mediated by glial TNF-α. Nature 2006, 440, 1054-1059, 10.1038/nature04671.
    6. Luan Pereira Diniz; Juliana Carvalho Almeida; Vanessa Tortelli; Charles Vargas Lopes; Pedro Setti-Perdigão; Joice Stipursky; Suzana Assad Kahn; Luciana Ferreira Romão; Joari De Miranda; Soniza Vieira Alves-Leon; et al. Astrocyte-induced Synaptogenesis Is Mediated by Transforming Growth Factor β Signaling through Modulation of d-Serine Levels in Cerebral Cortex Neurons. Journal of Biological Chemistry 2012, 287, 41432-41445, .
    7. Luan Pereira Diniz; Isadora C. Pereira Matias; Matheus Nunes Garcia; Flávia Carvalho Alcantara Gomes; Astrocytic control of neural circuit formation: Highlights on TGF-beta signaling. Neurochemistry International 2014, 78, 18-27, 10.1016/j.neuint.2014.07.008.
    8. Luan Pereira Diniz; Vanessa Tortelli; Matheus Nunes Garcia; Ana Paula Bérgamo Araújo; Helen M. Melo; Gisele S. Seixas Da Silva; Fernanda G. De Felice; Soniza Vieira Alves-Leon; Jorge Marcondes De Souza; Luciana Ferreira Romão; et al. Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling. Glia 2014, 62, 1917-1931, 10.1002/glia.22713.
    9. Luan Pereira Diniz; Vanessa Tortelli; Isadora Matias; Juliana Morgado; Ana Paula Bérgamo Araujo; Helen M. Melo; Gisele S. Seixas Da Silva; Soniza Vieira Alves-Leon; Jorge Marcondes De Souza; Sergio T. Ferreira; et al. Astrocyte Transforming Growth Factor Beta 1 Protects Synapses against Aβ Oligomers in Alzheimer's Disease Model. The Journal of Neuroscience 2017, 37, 6797-6809, 10.1523/jneurosci.3351-16.2017.
    10. Araque Alfonso; Astrocytes potentiate transmitter release at single hippocampal synapses. Frontiers in Neuroscience 2009, 3, 1083-1086, 10.3389/conf.neuro.01.2009.16.163.
    11. Alfonso Araque; Giorgio Carmignoto; Philip G. Haydon; Stéphane H. R. Oliet; Richard Robitaille; Andrea Volterra; Gliotransmitters Travel in Time and Space. Neuron 2014, 81, 728-739, 10.1016/j.neuron.2014.02.007.
    12. Marta Navarrete; Gertrudis Perea; David Fernandez De Sevilla; Marta Gómez-Gonzalo; Angel Núñez; Eduardo D. Martín; Alfonso Araque; Astrocytes Mediate In Vivo Cholinergic-Induced Synaptic Plasticity. PLoS Biology 2012, 10, e1001259, 10.1371/journal.pbio.1001259.
    13. C. Justin Lee; Guido Mannaioni; Hongjie Yuan; Dong Ho Woo; Melissa B. Gingrich; Stephen F. Traynelis; Astrocytic control of synaptic NMDA receptors. The Journal of Physiology 2007, 581, 1057-1081, 10.1113/jphysiol.2007.130377.
    14. Alexei Verkhratsky; Vladimir Parpura; José J. Rodríguez; Where the thoughts dwell: The physiology of neuronal–glial “diffuse neural net”. Brain Research Reviews 2011, 66, 133-151, 10.1016/j.brainresrev.2010.05.002.
    15. Michael V. Sofroniew; Harry V. Vinters; Astrocytes: biology and pathology. Acta Neuropathologica 2009, 119, 7-35, 10.1007/s00401-009-0619-8.
    16. Marta Gómez-Gonzalo; Tamara Zehnder; Linda Maria Requie; Paola Bezzi; Giorgio Carmignoto; Insights into the release mechanism of astrocytic glutamate evoking in neurons NMDA receptor-mediated slow depolarizing inward currents. Glia 2018, 66, 2188-2199, 10.1002/glia.23473.
    17. Sara Mederos; Gertrudis Perea; GABAergic‐astrocyte signaling: A refinement of inhibitory brain networks. Glia 2019, 67, 1842-1851, 10.1002/glia.23644.
    18. So-Young Lee; Philip G. Haydon; Astrocytic glutamate targets NMDA receptors. The Journal of Physiology 2007, 581, 887-888, 10.1113/jphysiol.2007.134676.
    19. Alexei Verkhratsky; Maiken Nedergaard; Physiology of Astroglia. Physiological Reviews 2018, 98, 239-389, 10.1152/physrev.00042.2016.
    20. Michele Siqueira; Daniel Francis; Diego Gisbert; Flávia Carvalho Alcantara Gomes; Joice Stipursky; Radial Glia Cells Control Angiogenesis in the Developing Cerebral Cortex Through TGF-β1 Signaling. Molecular Neurobiology 2017, 55, 1-16, 10.1007/s12035-017-0557-8.
    21. Brian A. MacVicar; Eric A. Newman; Astrocyte Regulation of Blood Flow in the Brain. Cold Spring Harbor Perspectives in Biology 2015, 7, a020388, 10.1101/cshperspect.a020388.
    22. Karan Govindpani; Laura G McNamara; Nicholas Smith; Chitra Vinnakota; Henry J. Waldvogel; Richard L.M. Faull; Andrea Kwakowsky; Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?. Journal of Clinical Medicine 2019, 8, 651, 10.3390/jcm8050651.
    23. Yasser Iturria-Medina; The Alzheimer’S Disease Neuroimaging Initiative; R. C. Sotero; P. J. Toussaint; J. M. Mateos-Pérez; A. C. Evans; Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nature Communications 2016, 7, 11934, 10.1038/ncomms11934.
    24. Melanie D. Sweeney; Abhay P. Sagare; Berislav V. Zlokovic; Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nature Reviews Neurology 2018, 14, 133-150, 10.1038/nrneurol.2017.188.
    25. Miriam Ries; Magdalena Sastre; Mechanisms of Aβ Clearance and Degradation by Glial Cells. Frontiers in Aging Neuroscience 2016, 8, 160, 10.3389/fnagi.2016.00160.
    26. Minghuan Wang; Fengfei Ding; Saiyue Deng; Xuequn Guo; Wei Wang; Jeffrey J. Iliff; Maiken Nedergaard; Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts. Journal of Neuroscience 2017, 37, 2870-2877, 10.1523/jneurosci.2112-16.2017.
    27. Benjamin T. Kress Ba; Jeffrey J. Iliff; Maosheng Xia; Minghuan Wang; Helen S. Wei; Douglas Zeppenfeld Bs; Lulu Xie; Hongyi Kang; Qiwu Xu; Jason A. Liew; et al. Impairment of paravascular clearance pathways in the aging brain. Annals of Neurology 2014, 76, 845-861, 10.1002/ana.24271.
    28. Zhiqiang Xu; Na Xiao; Yali Chen; Huang Huang; Charles Marshall; Junying Gao; Zhiyou Cai; Ting Wu; Gang Hu; Ming Xiao; et al. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Molecular Neurodegeneration 2015, 10, 1-16, 10.1186/s13024-015-0056-1.
    29. Milos Pekny; Marcela Pekna; Albee Messing; Christian Steinhäuser; Jin-Moo Lee; Vladimir Parpura; Elly M. Hol; Michael V. Sofroniew; Alexei Verkhratsky; Astrocytes: a central element in neurological diseases. Acta Neuropathologica 2015, 131, 323-345, 10.1007/s00401-015-1513-1.
    30. Alexei Verkhratsky; Robert Zorec; Vladimir Parpura; Stratification of astrocytes in healthy and diseased brain. Brain Pathology 2017, 27, 629-644, 10.1111/bpa.12537.
    31. Bianca Brawek; Robert Chesters; Daniel Klement; Julia Müller; Chommanad Lerdkrai; Marina Hermes; Olga Garaschuk; A bell-shaped dependence between amyloidosis and GABA accumulation in astrocytes in a mouse model of Alzheimer's disease. Neurobiology of Aging 2018, 61, 187-197, 10.1016/j.neurobiolaging.2017.09.028.
    32. Seonmi Jo; Oleg Yarishkin; Yu Jin Hwang; Ye Eun Chun; Mijeong Park; Dong Ho Woo; Jin Young Bae; Taekeun Kim; Jaekwang Lee; Heejung Chun; et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. Nature Medicine 2014, 20, 886-896, 10.1038/nm.3639.
    33. Olga Garaschuk; Alexei Verkhratsky; GABAergic astrocytes in Alzheimer’s disease. Aging 2019, 11, 1602-1604, 10.18632/aging.101870.
    34. Zheng Wu; Ziyuan Guo; Marla Gearing; Gong Chen; Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model. Nature Communications 2014, 5, 1-13, 10.1038/ncomms5159.
    35. Moonhee Lee; Claudia Schwab; Patrick L McGeer; Astrocytes are GABAergic cells that modulate microglial activity. Glia 2010, 59, 152-165, 10.1002/glia.21087.
    36. Silvia Holmseth; Yvette Dehnes; Yanhua H. Huang; Virginie V. Follin-Arbelet; Nina J. Grutle; Maria N. Mylonakou; Celine Plachez; Yun Zhou; David N. Furness; Dwight E. Bergles; et al. The Density of EAAC1 (EAAT3) Glutamate Transporters Expressed by Neurons in the Mammalian CNS. The Journal of Neuroscience 2012, 32, 6000-6013, 10.1523/jneurosci.5347-11.2012.
    37. Alan S. Hazell; Astrocytes are a major target in thiamine deficiency and Wernicke's encephalopathy. Neurochemistry International 2009, 55, 129-135, 10.1016/j.neuint.2009.02.020.
    38. Alan S. Hazell; Donna Sheedy; Raluca Oanea; Meghmik Aghourian; S. Sun; Jee Yong Jung; Dongmei Wang; Chunlei Wang; Loss of astrocytic glutamate transporters in Wernicke encephalopathy. Glia 2009, 58, 148-156, 10.1002/glia.20908.
    39. E. Masliah; L. Hansen; M. Alford; R. DeTeresa; M. Mallory; Deficient glutamate tranport is associated with neurodegeneration in Alzheimer's disease. Annals of Neurology 1996, 40, 759-766, 10.1002/ana.410400512.
    40. Yuji Ikegaya; Sigeru Matsuura; Sayaka Ueno; Atsushi Baba; Maki K. Yamada; Nobuyoshi Nishiyama; Norio Matsuki; β-Amyloid Enhances Glial Glutamate Uptake Activity and Attenuates Synaptic Efficacy. Journal of Biological Chemistry 2002, 277, 32180-32186, 10.1074/jbc.m203764200.
    41. Amanda L. Sheldon; Michael B. Robinson; The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochemistry International 2007, 51, 333-355, 10.1016/j.neuint.2007.03.012.
    42. Kou Takahashi; Joshua B. Foster; Chien-Liang Glenn Lin; Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cellular and Molecular Life Sciences 2015, 72, 3489-3506, 10.1007/s00018-015-1937-8.
    43. Filippo Ugolini; Daniele Lana; Pamela Nardiello; Daniele Nosi; Daniela Pantano; Fiorella Casamenti; Maria Giovannini; Different Patterns of Neurodegeneration and Glia Activation in CA1 and CA3 Hippocampal Regions of TgCRND8 Mice. Frontiers in Aging Neuroscience 2018, 10, 372, 10.3389/fnagi.2018.00372.
    44. Amaia M Arranz; Bart De Strooper; The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications. The Lancet Neurology 2019, 18, 406-414, 10.1016/s1474-4422(18)30490-3.
    45. Alexei Verkhratsky; Markel Olabarria; Harun N. Noristani; Chia-Yu Yeh; José J. Rodríguez; Astrocytes in Alzheimer’s disease. Neurotherapeutics 2010, 7, 399-412, 10.1016/j.nurt.2010.05.017.
    46. Alexei Verkhratsky; Amelia Marutle; J. J. Rodríguez-Arellano; Agneta Nordberg; Glial Asthenia and Functional Paralysis. The Neuroscientist 2014, 21, 552-568, 10.1177/1073858414547132.
    47. Markel Olabarria; Harun N. Noristani; Alexei Verkhratsky; José J. Rodríguez; Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia 2010, 58, 831-838, 10.1002/glia.20967.
    48. Magdalena Kulijewicz-Nawrot; Alexei Verkhratsky; Alexander Chvátal; Eva Syková; José J. Rodríguez; Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. Journal of Anatomy 2012, 221, 252-262, 10.1111/j.1469-7580.2012.01536.x.
    49. Chia-Yu Yeh; Bhamini Vadhwana; Alexei Verkhratsky; José J. Rodríguez; Early Astrocytic Atrophy in the Entorhinal Cortex of a Triple Transgenic Animal Model of Alzheimer's Disease. ASN Neuro 2011, 3, AN20110025-9, 10.1042/an20110025.
    50. L Meda; Glial activation in Alzheimer's disease: the role of Aβ and its associated proteins. Neurobiology of Aging 2001, 22, 885-893, 10.1016/s0197-4580(01)00307-4.
    51. Robert E. Mrak; W. Sue T. Griffin; Glia and their cytokines in progression of neurodegeneration. Neurobiology of Aging 2005, 26, 349-354, 10.1016/j.neurobiolaging.2004.05.010.
    52. Shane A. Liddelow; Ben A. Barres; Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity 2017, 46, 957-967, 10.1016/j.immuni.2017.06.006.
    53. Shane A. Liddelow; Kevin A. Guttenplan; Laura E. Clarke; Frederick C. Bennett; Shane A. Liddelow Christopher J. Bohlen; Lucas Schirmer; Mariko L. Bennett; Alexandra E. Münch; Won-Suk Chung; Todd C. Peterson; et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017, 541, 481-487, 10.1038/nature21029.
    54. Michael V. Sofroniew; Multiple Roles for Astrocytes as Effectors of Cytokines and Inflammatory Mediators. The Neuroscientist 2013, 20, 160-172, 10.1177/1073858413504466.
    55. Andrew W. Kraft; Xiaoyan Hu; Hyejin Yoon; Ping Yan; Qingli Xiao; Yan Wang; So Chon Gil; Jennifer Brown; Ulrika Wilhelmsson; Jessica L. Restivo; et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. The FASEB Journal 2012, 27, 187-198, 10.1096/fj.12-208660.
    56. Amy J. Gleichman; S. Thomas Carmichael; Glia in neurodegeneration: Drivers of disease or along for the ride?. Neurobiology of Disease 2020, 142, 104957, 10.1016/j.nbd.2020.104957.
    57. Jason G. Emsley; Jeffrey D. Macklis; Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biology 2006, 2, 175-186, 10.1017/s1740925x06000202.
    58. Ana Bribian; Fernando Pérez-Cerdá; Carlos Matute; Laura López-Mascaraque; Clonal Glial Response in a Multiple Sclerosis Mouse Model. Frontiers in Cellular Neuroscience 2018, 12, 375, 10.3389/fncel.2018.00375.
    59. Eduardo Martín-López; Jorge García-Marques; Raúl Núñez-Llaves; Laura López-Mascaraque; Clonal Astrocytic Response to Cortical Injury. PLOS ONE 2013, 8, e74039, 10.1371/journal.pone.0074039.
    60. Matthew M. Boisvert; Galina A. Erikson; Maxim N. Shokhirev; Nicola J. Allen; The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain. Cell Reports 2018, 22, 269-285, 10.1016/j.celrep.2017.12.039.
    61. Laura E. Clarke; Shane A. Liddelow; Chandrani Chakraborty; Alexandra E. Münch; Myriam Heiman; Ben A. Barres; Normal aging induces A1-like astrocyte reactivity. Proceedings of the National Academy of Sciences 2018, 115, E1896-E1905, 10.1073/pnas.1800165115.
    62. Ahmet Höke; David R. Canning; Charles J. Malemud; Jerry Silver; Regional Differences in Reactive Gliosis Induced by Substrate-Bound β-Amyloid. Experimental Neurology 1994, 130, 56-66, 10.1006/exnr.1994.1185.
    63. Hua Chai; Blanca Diaz-Castro; Eiji Shigetomi; Emma Monte; J. Christopher Octeau; Xinzhu Yu; Whitaker Cohn; Pradeep S. Rajendran; Thomas M. Vondriska; Julian P. Whitelegge; et al. Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence. Neuron 2017, 95, 531-549.e9, 10.1016/j.neuron.2017.06.029.
    64. Noriko Itoh; Yuichiro Itoh; Alessia Tassoni; Emily Ren; Max Kaito; Ai Ohno; Yan Ao; Vista Farkhondeh; Hadley Johnsonbaugh; Josh Burda; et al. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proceedings of the National Academy of Sciences 2017, 115, E302-E309, 10.1073/pnas.1716032115.
    65. Chia-Ching John Lin; Kwanha Yu; Asante Hatcher; Teng-Wei Huang; Hyun Kyoung Lee; Jeffrey Carlson; Matthew C Weston; Fengju Chen; Yiqun Zhang; Wenyi Zhu; et al. Identification of diverse astrocyte populations and their malignant analogs. Nature Neuroscience 2017, 20, 396-405, 10.1038/nn.4493.
    66. Darin Lanjakornsiripan; Baek-Jun Pior; Daichi Kawaguchi; Shohei Furutachi; Tomoaki Tahara; Yu Katsuyama; Yutaka Suzuki; Yugo Fukazawa; Yukiko Gotoh; Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers. Nature Communications 2018, 9, 1-15, 10.1038/s41467-018-03940-3.
    67. Lydie Morel; Ming Sum R. Chiang; Haruki Higashimori; Temitope Shoneye; Lakshmanan K. Iyer; Julia Yelick; Albert K. Tai; Yongjie Yang; Molecular and Functional Properties of Regional Astrocytes in the Adult Brain. The Journal of Neuroscience 2017, 37, 8706-8717, 10.1523/jneurosci.3956-16.2017.
    68. Makio Torigoe; Kenta Yamauchi; Yan Zhu; Hiroaki Kobayashi; Fujio Murakami; Association of astrocytes with neurons and astrocytes derived from distinct progenitor domains in the subpallium. Scientific Reports 2015, 5, 12258, 10.1038/srep12258.
    69. Alexandria N. Early; Amy A. Gorman; Linda J. Van Eldik; Adam D. Bachstetter; Josh M. Morganti; Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice. Journal of Neuroinflammation 2020, 17, 1-16, 10.1186/s12974-020-01800-w.
    70. Francesca Cerbai; Daniele Lana; Daniele Nosi; Polina Petkova-Kirova; Sandra Zecchi; Holly M. Brothers; Gary L. Wenk; Maria Giovannini; The Neuron-Astrocyte-Microglia Triad in Normal Brain Ageing and in a Model of Neuroinflammation in the Rat Hippocampus. PLoS ONE 2012, 7, e45250, 10.1371/journal.pone.0045250.
    71. Raffaella Mercatelli; Daniele Lana; Monica Bucciantini; Maria Grazia Giovannini; Francesca Cerbai; Franco Quercioli; Sandra Zecchi‐Orlandini; Giovanni Delfino; Gary L. Wenk; Daniele Nosi; et al. Clasmatodendrosis and β‐amyloidosis in aging hippocampus. The FASEB Journal 2015, 30, 1480-1491, 10.1096/fj.15-275503.
    72. Hea Jin Ryu; Ji-Eun Kim; Seong-Il Yeo; Tae-Cheon Kang; p65/RelA-Ser529 NF-κB Subunit Phosphorylation Induces Autophagic Astroglial Death (Clasmatodendrosis) Following Status Epilepticus. Cellular and Molecular Neurobiology 2011, 31, 1071-1078, 10.1007/s10571-011-9706-1.
    73. Kentaro Sakai; Takahiro Fukuda; Kimiharu Iwadate; Beading of the astrocytic processes (clasmatodendrosis) following head trauma is associated with protein degradation pathways. Brain Injury 2013, 27, 1692-1697, 10.3109/02699052.2013.837198.
    74. Duk-Soo Kim; Ji-Eun Kim; Sung-Eun Kwak; Kyung-Chan Choi; Dae-Won Kim; Oh-Shin Kwon; Soo Young Choi; Tae-Cheon Kang; Spatiotemporal characteristics of astroglial death in the rat hippocampo-entorhinal complex following pilocarpine-induced status epilepticus. Journal of Comparative Neurology 2008, 511, 581-598, 10.1002/cne.21878.
    75. H. Tomimoto; Ichiro Akiguchi; Hideaki Wakita; Toshihiko Suenaga; Shinichi Nakamura; Jun Kimura; Regressive changes of astroglia in white matter lesions in cerebrovascular disease and Alzheimer's disease patients. Acta Neuropathologica 1997, 94, 146-152, 10.1007/s004010050686.
    76. Demetrios J. Sahlas; Juan M. Bilbao; Richard H. Swartz; Sandra E. Black; Clasmatodendrosis correlating with periventricular hyperintensity in mixed dementia. Annals of Neurology 2002, 52, 378-381, 10.1002/ana.10310.
    77. Xiaoyan Jiang; Anuska V. Andjelkovic; Ling Zhu; Tuo Yang; Michael V.L. Bennett; Jun Chen; Richard F. Keep; Yejie Shi; Blood-brain barrier dysfunction and recovery after ischemic stroke. Progress in Neurobiology 2018, 163-164, 144-171, 10.1016/j.pneurobio.2017.10.001.
    78. Dan Frenkel; Kim Wilkinson; Lingzhi Zhao; Suzanne E. Hickman; Terry K. Means; Lindsay Puckett; Dorit Farfara; Nathan D. Kingery; Howard L. Weiner; Joseph El Khoury; et al. Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nature Communications 2013, 4, 1-9, 10.1038/ncomms3030.
    79. Fernanda Marques; João Carlos Sousa; Nuno Sousa; Joana Almeida Palha; Blood–brain-barriers in aging and in Alzheimer’s disease. Molecular Neurodegeneration 2013, 8, 38-38, 10.1186/1750-1326-8-38.
    80. Robert G Nagele; Jerzy Wegiel; Venkat Venkataraman; Humi Imaki; Kuo-Chiang Wang; Jarek Wegiel; Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiology of Aging 2004, 25, 663-674, 10.1016/j.neurobiolaging.2004.01.007.
    81. Rodrigo E. González-Reyes; Mauricio O. Nava-Mesa; Karina Vargas-Sánchez; Daniel Ariza-Salamanca; Laura Mora-Muñoz; Involvement of Astrocytes in Alzheimer’s Disease from a Neuroinflammatory and Oxidative Stress Perspective. Frontiers in Molecular Neuroscience 2017, 10, 427, 10.3389/fnmol.2017.00427.
    82. Raasay S. Jones; Aedín M. Minogue; Thomas J. Connor; Marina A. Lynch; Amyloid-β-Induced Astrocytic Phagocytosis is Mediated by CD36, CD47 and RAGE. Journal of Neuroimmune Pharmacology 2012, 8, 301-311, 10.1007/s11481-012-9427-3.
    83. Carla Ecirillo; Elena Capoccia; Teresa Iuvone; R. Cuomo; Giovanni Alessandra D&rsquo Giovanni Sarnelli; Luca Steardo; Giuseppe Esposito; S100B Inhibitor Pentamidine Attenuates Reactive Gliosis and Reduces Neuronal Loss in a Mouse Model of Alzheimer’s Disease. BioMed Research International 2015, 2015, 1-11, 10.1155/2015/508342.
    84. Lars-Ove Brandenburg; Maximilian Konrad; Christoph J. Wruck; Thomas Koch; Ralph Lucius; Thomas Pufe; Functional and physical interactions between formyl-peptide-receptors and scavenger receptor MARCO and their involvement in amyloid beta 1-42-induced signal transduction in glial cells. Journal of Neurochemistry 2010, 113, 749-760, 10.1111/j.1471-4159.2010.06637.x.
    85. Kim Wilkinson; Joseph El Khoury; Microglial Scavenger Receptors and Their Roles in the Pathogenesis of Alzheimer's Disease. International Journal of Alzheimer's Disease 2012, 2012, 1-10, 10.1155/2012/489456.
    86. Cameron R. Stewart; Lynda M. Stuart; Kim Wilkinson; Janine M. Van Gils; Jiusheng Deng; Annett Halle; Katey J. Rayner; Laurent Boyer; Ruiqin Zhong; William A. Frazier; et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunology 2009, 11, 155-161, 10.1038/ni.1836.
    87. Carole Escartin; Océane Guillemaud; Maria‐Angeles Carrillo‐De Sauvage; Questions and (some) answers on reactive astrocytes. Glia 2019, 67, 2221-2247, 10.1002/glia.23687.
    88. Milos Pekny; Marcela Pekna; Astrocyte Reactivity and Reactive Astrogliosis: Costs and Benefits. Physiological Reviews 2014, 94, 1077-1098, 10.1152/physrev.00041.2013.
    89. Hsiao-Huei Wu; Elena Bellmunt; Jami L. Scheib; Victor Venegas; Cornelia Burkert; Louis F. Reichardt; Zheng Zhou; Isabel Fariñas; Bruce D. Carter; Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nature Neuroscience 2009, 12, 1534-1541, 10.1038/nn.2446.
    90. Zhenjie Lu; Michael R. Elliott; Yubo Chen; James T. Walsh; Alexander L. Klibanov; Kodi S. Ravichandran; Jonathan Kipnis; Phagocytic activity of neuronal progenitors regulates adult neurogenesis. Nature 2011, 13, 1076-1083, 10.1038/ncb2299.
    91. Tal Iram; Zaida Ramirez-Ortiz; Michael H. Byrne; Uwanda A. Coleman; Nathan D. Kingery; Terry K. Means; Dan Frenkel; Joseph El Khoury; Megf10 Is a Receptor for C1Q That Mediates Clearance of Apoptotic Cells by Astrocytes. Journal of Neuroscience 2016, 36, 5185-5192, 10.1523/jneurosci.3850-15.2016.
    92. Yosuke M. Morizawa; Yuri Hirayama; Nobuhiko Ohno; Shinsuke Shibata; Eiji Shigetomi; Yang Sui; Junichi Nabekura; Koichi Sato; Fumikazu Okajima; Hirohide Takebayashi; et al. Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. Nature Communications 2017, 8, 1-15, 10.1038/s41467-017-00037-1.
    93. Nicole M. Wakida; Gladys Mae S. Cruz; Clarissa C. Ro; Emmanuel G. Moncada; Nima Khatibzadeh; Lisa A. Flanagan; Michael W. Berns; Phagocytic response of astrocytes to damaged neighboring cells. PLOS ONE 2018, 13, e0196153, 10.1371/journal.pone.0196153.
    94. Won-Suk Chung; Laura E. Clarke; Gordon X. Wang; Benjamin K. Stafford; Alexander Sher; Chandrani Chakraborty; Julia Joung; Lynette C. Foo; Andrew Thompson; Chinfei Chen; et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 2013, 504, 394-400, 10.1038/nature12776.
    95. Daeho Park; Annie-Carole Tosello-Trampont; Michael R. Elliott; Mingjian Lu; Lisa B. Haney; Zhong Ma; Alexander L. Klibanov; James W. Mandell; Kodi S. Ravichandran; BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 2007, 450, 430-434, 10.1038/nature06329.
    96. Axel Nimmerjahn; Frank Kirchhoff; Fritjof Helmchen; Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo. Science 2005, 308, 1314-1318, 10.1126/science.1110647.
    97. Seiji Okada; Conditional ablation of stat3/socs3 discloses the dual role for reactive astrocytes after spinal cord injury. Protocol Exchange 2006, 12, 829-834, 10.1038/nprot.2006.155.
    98. Angela Gomez-Arboledas; Jose C. Davila; Elisabeth Sanchez-Mejias; Victoria Navarro; Cristina Nuñez-Diaz; Raquel Sanchez-Varo; Maria Virtudes Sanchez-Mico; Laura Trujillo-Estrada; Juan Jose Fernandez-Valenzuela; Marisa Vizuete; et al. Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease. Glia 2017, 66, 637-653, 10.1002/glia.23270.
    99. Imrich Blasko; Michaela Stampfer-Kountchev; Peter Robatscher; Robert Veerhuis; Piet Eikelenboom; Beatrix Grubeck-Loebenstein; How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes. Aging Cell 2004, 3, 169-176, 10.1111/j.1474-9728.2004.00101.x.
    100. Rekha Bhat; Elizabeth P. Crowe; Alessandro Bitto; Michelle Moh; Christos D. Katsetos; Fernando U. Garcia; Frederick Bradley Johnson; John Q. Trojanowski; Christian Sell; Claudio Torres; et al. Astrocyte Senescence as a Component of Alzheimer’s Disease. PLOS ONE 2012, 7, e45069, 10.1371/journal.pone.0045069.
    101. Jie Zhao; Tracy O. Connor; Robert Vassar; The contribution of activated astrocytes to Aβ production: Implications for Alzheimer's disease pathogenesis. Journal of Neuroinflammation 2011, 8, 150-150, 10.1186/1742-2094-8-150.
    102. Georgia R. Frost; Yue-Ming Li; The role of astrocytes in amyloid production and Alzheimer's disease. Open Biology 2017, 7, 170228, 10.1098/rsob.170228.
    103. D. Ourdev; A. Schmaus; Satyabrata Kar; Kainate Receptor Activation Enhances Amyloidogenic Processing of APP in Astrocytes. Molecular Neurobiology 2018, 56, 5095-5110, 10.1007/s12035-018-1427-8.
    104. Chia-Yu Yeh; Bhamini Vadhwana; Alexei Verkhratsky; José J. Rodríguez; Early Astrocytic Atrophy in the Entorhinal Cortex of a Triple Transgenic Animal Model of Alzheimer's Disease. ASN Neuro 2011, 3, 271-279, 10.1042/an20110025.
    105. Juan Beauquis; Patricio Pavía; Carlos Pomilio; Angeles Vinuesa; Natalia Podlutskaya; Veronica Galvan; Flavia Saravia; Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer's disease. Experimental Neurology 2013, 239, 28-37, 10.1016/j.expneurol.2012.09.009.
    106. Robert G Nagele; Michael R. D’Andrea; H. Lee; Venkateswar Venkataraman; Hoau-Yan Wang; Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Research 2003, 971, 197-209, 10.1016/s0006-8993(03)02361-8.
    107. J. J. Rodríguez; M Olabarria; Alexandr Chvátal; Alexei Verkhratsky; J J Rodr; Astroglia in dementia and Alzheimer's disease. Cell Death & Differentiation 2008, 16, 378-385, 10.1038/cdd.2008.172.
    108. José J. Rodríguez; Chia-Yu Yeh; Slavica Terzieva; Markel Olabarria; Magdalena Kulijewicz-Nawrot; Alexei Verkhratsky; Complex and region-specific changes in astroglial markers in the aging brain. Neurobiology of Aging 2014, 35, 15-23, 10.1016/j.neurobiolaging.2013.07.002.
    109. Kunyu Li; Jiatong Li; Jialin Zheng; Song Qin; Reactive Astrocytes in Neurodegenerative Diseases. Aging and disease 2019, 10, 664-675, 10.14336/ad.2018.0720.
    More