Abstract
Astrocytes are the most abundant cells in the central nervous system (CNS). Under neurodegenerative conditions, astrocytes can go through various morphological and functional changes and then transform into reactive forms. Therefore, compared with normal physiological conditions, the expression and distribution of many cellular molecules in reactive astrocytes show significant changes. It will be of great benefit for research and clinical practice if these molecular alterations of astrocytes can be used as biomarkers for the study of neurodegenerative diseases. In this chapter, we will comprehensively introduce some potential biomarkers involving various aspects of activated astrocytes, including structural and functional characteristics, and their participation in neuroinflammatory responses, such as GFAP, glutamate transporters, and S100β. We will analyze the advantages and limitations of traditional biomarkers of reactive astrocytes, such as GFAP, and provide some insights into potentially novel biomarkers. Then we will give a brief introduction of potential biomarkers in some typical neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Finally, we provide some methods applied in biomarker studies for reference. These methods range from astrocyte isolating, culture, and further biomarker analysis to clinical techniques such as molecular imaging. In the future, advances in the detection of biomarkers in astrocytes under neurodegenerative conditions will not only shed light on early diagnosis but also be illuminating in the treatment of neurodegenerative diseases, which is still in a rather difficult stage, by serving as potential targets for drugs. More analyses of astrocytes based on these biomarkers and a deeper understanding of the molecular pathogenesis of neurodegenerative diseases will undoubtedly bring hope to individual patients, their families, and the whole society as well.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Whalley K (2014) Neurodegenerative disease: propagating pathology. Nat Rev Neurosci 15(9):565. https://doi.org/10.1038/nrn3802
Montie HL, Durcan TM (2013) The cell and molecular biology of neurodegenerative diseases: an overview. Front Neurol 4:194. https://doi.org/10.3389/fneur.2013.00194
Li K, Li J, Zheng J, Qin S (2019) Reactive astrocytes in neurodegenerative diseases. Aging Dis 10(3):664–675. https://doi.org/10.14336/AD.2018.0720
Wyss-Coray T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539(7628):180–186. https://doi.org/10.1038/nature20411
Fakhoury M (2018) Microglia and astrocytes in Alzheimer’s disease: implications for therapy. Curr Neuropharmacol 16(5):508–518. https://doi.org/10.2174/1570159X15666170720095240
Jung CK, Keppler K, Steinbach S, Blazquez-Llorca L, Herms J (2015) Fibrillar amyloid plaque formation precedes microglial activation. PLoS One 10(3):e0119768. https://doi.org/10.1371/journal.pone.0119768
Ries M, Sastre M (2016) Mechanisms of abeta clearance and degradation by glial cells. Front Aging Neurosci 8:160. https://doi.org/10.3389/fnagi.2016.00160
Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F et al (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9(4):453–457. https://doi.org/10.1038/nm838
Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW et al (2015) NFkappaB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85(1):101–115. https://doi.org/10.1016/j.neuron.2014.11.018
Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140(6):918–934. https://doi.org/10.1016/j.cell.2010.02.016
Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6(4):193–201. https://doi.org/10.1038/nrneurol.2010.17
Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94(4):1077–1098. https://doi.org/10.1152/physrev.00041.2013
De Strooper B, Karran E (2016) The cellular phase of Alzheimer’s disease. Cell 164(4):603–615. https://doi.org/10.1016/j.cell.2015.12.056
Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35. https://doi.org/10.1007/s00401-009-0619-8
Muller HW, Matthiessen HP, Schmalenbach C, Schroeder WO (1991) Glial support of CNS neuronal survival, neurite growth and regeneration. Restor Neurol Neurosci 2(4):229–232. https://doi.org/10.3233/RNN-1991-245610
Yang D, Peng C, Li X, Fan X, Li L, Ming M et al (2008) Pitx3-transfected astrocytes secrete brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and protect dopamine neurons in mesencephalon cultures. J Neurosci Res 86(15):3393–3400. https://doi.org/10.1002/jnr.21774
Gengatharan A, Bammann RR, Saghatelyan A (2016) The role of astrocytes in the generation, migration, and integration of new neurons in the adult olfactory bulb. Front Neurosci 10:149. https://doi.org/10.3389/fnins.2016.00149
Theodosis DT, Piet R, Poulain DA, Oliet SH (2004) Neuronal, glial and synaptic remodeling in the adult hypothalamus: functional consequences and role of cell surface and extracellular matrix adhesion molecules. Neurochem Int 45(4):491–501. https://doi.org/10.1016/j.neuint.2003.11.003
Inyushin M, Kucheryavykh LY, Kucheryavykh YV, Nichols CG, Buono RJ, Ferraro TN et al (2010) Potassium channel activity and glutamate uptake are impaired in astrocytes of seizure-susceptible DBA/2 mice. Epilepsia 51(9):1707–1713. https://doi.org/10.1111/j.1528-1167.2010.02592.x
Gadea A, Schinelli S, Gallo V (2008) Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. J Neurosci 28(10):2394–2408. https://doi.org/10.1523/JNEUROSCI.5652-07.2008
Levison SW, Jiang FJ, Stoltzfus OK, Ducceschi MH (2000) IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation. Glia 32(3):328–337. https://doi.org/10.1002/1098-1136(200012)32:3<328::aid-glia110>3.0.co;2-7
Rodriguez JJ, Yeh CY, Terzieva S, Olabarria M, Kulijewicz-Nawrot M, Verkhratsky A (2014) Complex and region-specific changes in astroglial markers in the aging brain. Neurobiol Aging 35(1):15–23. https://doi.org/10.1016/j.neurobiolaging.2013.07.002
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487. https://doi.org/10.1038/nature21029
Forster S, Grimmer T, Miederer I, Henriksen G, Yousefi BH, Graner P et al (2012) Regional expansion of hypometabolism in Alzheimer’s disease follows amyloid deposition with temporal delay. Biol Psychiatry 71(9):792–797. https://doi.org/10.1016/j.biopsych.2011.04.023
Yao J, Rettberg JR, Klosinski LP, Cadenas E, Brinton RD (2011) Shift in brain metabolism in late onset Alzheimer’s disease: implications for biomarkers and therapeutic interventions. Mol Asp Med 32(4–6):247–257. https://doi.org/10.1016/j.mam.2011.10.005
Matarin M, Salih DA, Yasvoina M, Cummings DM, Guelfi S, Liu W et al (2015) A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep 10(4):633–644. https://doi.org/10.1016/j.celrep.2014.12.041
Karch CM, Cruchaga C, Goate AM (2014) Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83(1):11–26. https://doi.org/10.1016/j.neuron.2014.05.041
Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W (2011) Astrocytes are important mediators of Abeta-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2:e167. https://doi.org/10.1038/cddis.2011.50
Jana A, Pahan K (2010) Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer’s disease. J Neurosci 30(38):12676–12689. https://doi.org/10.1523/JNEUROSCI.1243-10.2010
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421. https://doi.org/10.1016/s0197-4580(00)00124-x
Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V et al (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131(3):323–345. https://doi.org/10.1007/s00401-015-1513-1
Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81(2):229–248. https://doi.org/10.1016/j.neuron.2013.12.034
Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38. https://doi.org/10.1016/j.neulet.2013.12.071
Seifert G, Schilling K, Steinhauser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7(3):194–206. https://doi.org/10.1038/nrn1870
Verkhratsky A, Sofroniew MV, Messing A, de Lanerolle NC, Rempe D, Rodriguez JJ et al (2012) Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 4(3). https://doi.org/10.1042/AN20120010
Vasile F, Dossi E, Rouach N (2017) Human astrocytes: structure and functions in the healthy brain. Brain Struct Funct 222(5):2017–2029
Taft JR, Vertes RP, Perry GW (2005) Distribution of GFAP+ astrocytes in adult and neonatal rat brain. Int J Neurosci 115(9):1333–1343. https://doi.org/10.1080/00207450590934570
Guillamon-Vivancos T, Gomez-Pinedo U, Matias-Guiu J (2015) Astrocytes in neurodegenerative diseases (I): function and molecular description. Neurologia 30(2):119–129. https://doi.org/10.1016/j.nrl.2012.12.007
Reeves SA, Helman LJ, Allison A, Israel MA (1989) Molecular cloning and primary structure of human glial fibrillary acidic protein. Proc Natl Acad Sci U S A 86(13):5178–5182. https://doi.org/10.1073/pnas.86.13.5178
Condorelli DF, Nicoletti VG, Barresi V, Conticello SG, Caruso A, Tendi EA et al (1999) Structural features of the rat GFAP gene and identification of a novel alternative transcript. J Neurosci Res 56(3):219–228. https://doi.org/10.1002/(SICI)1097-4547(19990501)56:3<219::AID-JNR1>3.0.CO;2-2
Zelenika D, Grima B, Brenner M, Pessac B (1995) A novel glial fibrillary acidic protein mRNA lacking exon 1. Brain Res Mol Brain Res 30(2):251–258. https://doi.org/10.1016/0169-328x(95)00010-p
Roelofs RF, Fischer DF, Houtman SH, Sluijs JA, Van Haren W, Van Leeuwen FW et al (2005) Adult human subventricular, subgranular, and subpial zones contain astrocytes with a specialized intermediate filament cytoskeleton. Glia 52(4):289–300. https://doi.org/10.1002/glia.20243
Nielsen AL, Holm IE, Johansen M, Bonven B, Jorgensen P, Jorgensen AL (2002) A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins. J Biol Chem 277(33):29983–29991. https://doi.org/10.1074/jbc.M112121200
Blechingberg J, Holm IE, Nielsen KB, Jensen TH, Jorgensen AL, Nielsen AL (2007) Identification and characterization of GFAPkappa, a novel glial fibrillary acidic protein isoform. Glia 55(5):497–507. https://doi.org/10.1002/glia.20475
Hol EM, Roelofs RF, Moraal E, Sonnemans MA, Sluijs JA, Proper EA et al (2003) Neuronal expression of GFAP in patients with Alzheimer pathology and identification of novel GFAP splice forms. Mol Psychiatry 8(9):786–796. https://doi.org/10.1038/sj.mp.4001379
van den Berge SA, Middeldorp J, Zhang CE, Curtis MA, Leonard BW, Mastroeni D et al (2010) Longterm quiescent cells in the aged human subventricular neurogenic system specifically express GFAP-delta. Aging Cell 9(3):313–326. https://doi.org/10.1111/j.1474-9726.2010.00556.x
Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97(6):703–716. https://doi.org/10.1016/s0092-8674(00)80783-7
Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S et al (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427(6976):740–744. https://doi.org/10.1038/nature02301
Quinones-Hinojosa A, Sanai N, Soriano-Navarro M, Gonzalez-Perez O, Mirzadeh Z, Gil-Perotin S et al (2006) Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J Comp Neurol 494(3):415–434. https://doi.org/10.1002/cne.20798
Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7(1):41–53
Ballabh P, Braun A, Nedergaard M (2004) The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16(1):1–13. https://doi.org/10.1016/j.nbd.2003.12.016
Allaman I, Belanger M, Magistretti PJ (2011) Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34(2):76–87. https://doi.org/10.1016/j.tins.2010.12.001
Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC (2014) Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol 11:13–30. https://doi.org/10.1007/978-3-319-08894-5_2
Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129(4):877–896. https://doi.org/10.1016/j.neuroscience.2004.09.053
Zador Z, Stiver S, Wang V, Manley GT (2009) Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol 190:159–170. https://doi.org/10.1007/978-3-540-79885-9_7
Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26(10):523–530. https://doi.org/10.1016/j.tins.2003.08.008
Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60(3):430–440
Borjabad A, Volsky DJ (2012) Common transcriptional signatures in brain tissue from patients with HIV-associated neurocognitive disorders, Alzheimer’s disease, and multiple sclerosis. J Neuroimmune Pharmacol 7(4):914–926. https://doi.org/10.1007/s11481-012-9409-5
Cotto B, Natarajaseenivasan K, Langford D (2019) Astrocyte activation and altered metabolism in normal aging, age-related CNS diseases, and HAND. J Neurovirol 25(5):722–733. https://doi.org/10.1007/s13365-019-00721-6
Wilhelmsson U, Bushong EA, Price DL, Smarr B, Phung V, Terada M et al (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci U S A 103(46):17513–17518
Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32(12):638–647. https://doi.org/10.1016/j.tins.2009.08.002
Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156. https://doi.org/10.1038/nrn1326
Bundesen LQ, Scheel TA, Bregman BS, Kromer LF (2003) Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J Neurosci 23(21):7789–7800
Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK et al (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28(28):7231–7243
Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN et al (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23(2):297–308. https://doi.org/10.1016/s0896-6273(00)80781-3
Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LB, Tiwari-Woodruff S et al (2009) Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci 29(37):11511–11522. https://doi.org/10.1523/JNEUROSCI.1514-09.2009
Hofmann SL, Das AK, Lu J, Wisniewski KE, Gupta P (2001) Infantile neuronal ceroid lipofuscinosis:no longer just a ‘Finnish’ disease. Eur J Paediatr Neurol 5:47–51
Hofmann SL, Das AK, Yi W, Lu JY, Wisniewski KE (1999) Genotype–phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. Mol Genet Metab 66(4):234–239
Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P et al (1995) Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376(6541):584–587. https://doi.org/10.1038/376584a0
Kielar C, Maddox L, Bible E, Pontikis CC, Macauley SL, Griffey MA et al (2007) Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 25(1):150–162. https://doi.org/10.1016/j.nbd.2006.09.001
Macauley SL, Wozniak DF, Kielar C, Tan Y, Cooper JD, Sands MS (2009) Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse. Exp Neurol 217(1):124–135. https://doi.org/10.1016/j.expneurol.2009.01.022
Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27(1):117–120. https://doi.org/10.1038/83679
Messing A, LaPash Daniels CM, Hagemann TL (2010) Strategies for treatment in Alexander disease. Neurotherapeutics 7(4):507–515. https://doi.org/10.1016/j.nurt.2010.05.013
Kamphuis W, Middeldorp J, Kooijman L, Sluijs JA, Kooi EJ, Moeton M et al (2014) Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer’s disease. Neurobiol Aging 35(3):492–510. https://doi.org/10.1016/j.neurobiolaging.2013.09.035
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259. https://doi.org/10.1007/BF00308809
Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184. https://doi.org/10.1146/annurev.neuro.051508.135600
Lutz SE, Zhao Y, Gulinello M, Lee SC, Raine CS, Brosnan CF (2009) Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation. J Neurosci 29(24):7743–7752. https://doi.org/10.1523/JNEUROSCI.0341-09.2009
Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews FE et al (2010) Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 31(4):578–590
Simpson JE, Ince PG, Shaw PJ, Heath PR, Raman R, Garwood CJ et al (2011) Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol Aging 32(10):1795–1807. https://doi.org/10.1016/j.neurobiolaging.2011.04.013
Gu XL, Long CX, Sun L, Xie C, Lin X, Cai H (2010) Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain 3:12. https://doi.org/10.1186/1756-6606-3-12
Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L et al (1998) Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20(3):589–602. https://doi.org/10.1016/s0896-6273(00)80997-6
Maragakis NJ, Dykes-Hoberg M, Rothstein JD (2004) Altered expression of the glutamate transporter EAAT2b in neurological disease. Ann Neurol 55(4):469–477. https://doi.org/10.1002/ana.20003
Alexander GM, Deitch JS, Seeburger JL, Del Valle L, Heiman-Patterson TD (2000) Elevated cortical extracellular fluid glutamate in transgenic mice expressing human mutant (G93A) Cu/Zn superoxide dismutase. J Neurochem 74(4):1666–1673. https://doi.org/10.1046/j.1471-4159.2000.0741666.x
Yang Y, Gozen O, Vidensky S, Robinson MB, Rothstein JD (2010) Epigenetic regulation of neuron-dependent induction of astroglial synaptic protein GLT1. Glia 58(3):277–286. https://doi.org/10.1002/glia.20922
Li K, Hala TJ, Seetharam S, Poulsen DJ, Wright MC, Lepore AC (2015) GLT1 overexpression in SOD1(G93A) mouse cervical spinal cord does not preserve diaphragm function or extend disease. Neurobiol Dis 78:12–23. https://doi.org/10.1016/j.nbd.2015.03.010
Bristol LA, Rothstein JD (1996) Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Ann Neurol 39(5):676–679. https://doi.org/10.1002/ana.410390519
Flowers JM, Powell J, Leigh PN, Andersen PM, Shaw C (2001) Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis. Ann Neurol 49(5):643–649
Jiang LL, Zhu B, Zhao Y, Li X, Liu T, Pina-Crespo J et al (2019) Membralin deficiency dysregulates astrocytic glutamate homeostasis leading to ALS-like impairment. J Clin Invest 129(8):3103–3120. https://doi.org/10.1172/JCI127695
Fray AE, Ince PG, Banner SJ, Milton ID, Usher PA, Cookson MR et al (1998) The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur J Neurosci 10(8):2481–2489. https://doi.org/10.1046/j.1460-9568.1998.00273.x
Estradasanchez AM, Rebec GV (2012) Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington’s disease: interactions between neurons and astrocytes. Basal Ganglia 2(2):57–66
Duerson K, Woltjer RL, Mookherjee P, Leverenz JB, Montine TJ, Bird TD et al (2009) Detergent-insoluble EAAC1/EAAT3 aberrantly accumulates in hippocampal neurons of Alzheimer’s disease patients. Brain Pathol 19(2):267–278. https://doi.org/10.1111/j.1750-3639.2008.00186.x
Lauderback CM, Hackett JM, Huang FF, Keller JN, Szweda LI, Markesbery WR et al (2001) The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer’s disease brain: the role of Aβ1–42. J Neurochem 78(2):413–416. https://doi.org/10.1046/j.1471-4159.2001.00451.x
Scott HA, Gebhardt FM, Mitrovic AD, Vandenberg RJ, Dodd PR (2011) Glutamate transporter variants reduce glutamate uptake in Alzheimer’s disease. Neurobiol Aging 32(3):553.e1–553.11. https://doi.org/10.1016/j.neurobiolaging.2010.03.008
Woltjer RL, Duerson K, Fullmer JM, Mookherjee P, Ryan AM, Montine TJ et al (2010) Aberrant detergent-insoluble excitatory amino acid transporter 2 accumulates in Alzheimer disease. J Neuropathol Exp Neurol 69(7):667–676. https://doi.org/10.1097/NEN.0b013e3181e24adb
Norenberg MD (1979) Distribution of glutamine synthetase in the rat central nervous system. J Histochem Cytochem 27(3):756–762. https://doi.org/10.1177/27.3.39099
Patel AJ, Weir MD, Hunt A, Tahourdin CS, Thomas DG (1985) Distribution of glutamine synthetase and glial fibrillary acidic protein and correlation of glutamine synthetase with glutamate decarboxylase in different regions of the rat central nervous system. Brain Res 331(1):1–9. https://doi.org/10.1016/0006-8993(85)90708-5
Rose CF, Verkhratsky A, Parpura V (2013) Astrocyte glutamine synthetase: pivotal in health and disease. Biochem Soc Trans 41(6):1518–1524. https://doi.org/10.1042/BST20130237
Li K-Y, Gong P-F, Li J-T, Xu N-J, Qin S (2020) Morphological and molecular alterations of reactive astrocytes without proliferation in cerebral cortex of an APP/PS1 transgenic mouse model and Alzheimer’s patients. Glia 68(11):2361–2376. https://doi.org/10.1002/glia.23845
Goncalves C, Leite MC, Nardin P (2008) Biological and methodological features of the measurement of S100B, a putative marker of brain injury. Clin Biochem 41(10):755–763
Marenholz I, Heizmann CW, Fritz G (2004) S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun 322(4):1111–1122. https://doi.org/10.1016/j.bbrc.2004.07.096
Donato R (2001) S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 33(7):637–668. https://doi.org/10.1016/s1357-2725(01)00046-2
Donato R (2003) Intracellular and extracellular roles of S100 proteins. Microsc Res Tech 60(6):540–551. https://doi.org/10.1002/jemt.10296
Harris JL, Yeh HW, Swerdlow RH, Choi IY, Lee P, Brooks WM (2014) High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging. Neurobiol Aging 35(7):1686–1694. https://doi.org/10.1016/j.neurobiolaging.2014.01.018
Harris JL, Choi IY, Brooks WM (2015) Probing astrocyte metabolism in vivo: proton magnetic resonance spectroscopy in the injured and aging brain. Front Aging Neurosci 7:202. https://doi.org/10.3389/fnagi.2015.00202
Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G et al (1994) Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 62(1):15–30. https://doi.org/10.1016/0306-4522(94)90311-5
Gulyas B, Pavlova E, Kasa P, Gulya K, Bakota L, Varszegi S et al (2011) Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-l-deprenyl using whole hemisphere autoradiography. Neurochem Int 58(1):60–68
Garwood CJ, Ratcliffe LE, Simpson JE, Heath PR, Ince PG, Wharton SB (2017) Review: Astrocytes in Alzheimer’s disease and other age-associated dementias: a supporting player with a central role. Neuropathol Appl Neurobiol 43(4):281–298. https://doi.org/10.1111/nan.12338
Liddelow SA, Barres BA (2017) Reactive astrocytes: production, function, and therapeutic potential. Immunity 46(6):957–967. https://doi.org/10.1016/j.immuni.2017.06.006
Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16(6):358–372. https://doi.org/10.1038/nrn3880
Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012:756357. https://doi.org/10.1100/2012/756357
Heneka MT, O’Banion MK, Terwel D, Kummer MP (2010) Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm (Vienna) 117(8):919–947. https://doi.org/10.1007/s00702-010-0438-z
Phillips EC, Croft CL, Kurbatskaya K, Oneill MJ, Hutton M, Hanger DP et al (2014) Astrocytes and neuroinflammation in Alzheimer’s disease. Biochem Soc Trans 42(5):1321–1325
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405. https://doi.org/10.1016/S1474-4422(15)70016-5
Gao Q, Li Y, Chopp M (2005) Bone marrow stromal cells increase astrocyte survival via upregulation of phosphoinositide 3-kinase/threonine protein kinase and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways and stimulate astrocyte trophic factor gene expression after anaerobic insult. Neuroscience 136(1):123–134. https://doi.org/10.1016/j.neuroscience.2005.06.091
Hayakawa K, Pham LD, Arai K, Lo EH (2014) Reactive astrocytes promote adhesive interactions between brain endothelium and endothelial progenitor cells via HMGB1 and beta-2 integrin signaling. Stem Cell Res 12(2):531–538
Borjabad A, Brooks AI, Volsky DJ (2010) Gene expression profiles of HIV-1-infected glia and brain: toward better understanding of the role of astrocytes in HIV-1-associated neurocognitive disorders. J Neuroimmune Pharmacol 5(1):44–62. https://doi.org/10.1007/s11481-009-9167-1
Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278. https://doi.org/10.1523/JNEUROSCI.4178-07.2008
Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR et al (2006) Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 281(34):24566–24574. https://doi.org/10.1074/jbc.M602440200
Yin KJ, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X et al (2006) Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 26(43):10939–10948. https://doi.org/10.1523/JNEUROSCI.2085-06.2006
John GR, Lee SC, Brosnan CF (2003) Cytokines: powerful regulators of glial cell activation. Neuroscientist 9(1):10–22. https://doi.org/10.1177/1073858402239587
Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10(5):608–614. https://doi.org/10.1038/nn1885
Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28(3):138–145. https://doi.org/10.1016/j.it.2007.01.005
Bekar LK, He W, Nedergaard M (2008) Locus coeruleus alpha-adrenergic-mediated activation of cortical astrocytes in vivo. Cereb Cortex 18(12):2789–2795. https://doi.org/10.1093/cercor/bhn040
Neary JT, Kang Y, Willoughby KA, Ellis EF (2003) Activation of extracellular signal-regulated kinase by stretch-induced injury in astrocytes involves extracellular ATP and P2 purinergic receptors. J Neurosci 23(6):2348–2356
Swanson RA, Ying W, Kauppinen TM (2004) Astrocyte influences on ischemic neuronal death. Curr Mol Med 4(2):193–205. https://doi.org/10.2174/1566524043479185
Norenberg MD, Rao KVR, Jayakumar AR (2009) Signaling factors in the mechanism of ammonia neurotoxicity. Metab Brain Dis 24(1):103–117
Migheli A, Piva R, Atzori C, Troost D, Schiffer D (1997) c-Jun, JNK/SAPK kinases and transcription factor NF-kappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 56(12):1314–1322
Gilmore TD (2006) Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 25(51):6680–6684. https://doi.org/10.1038/sj.onc.1209954
Ceyzeriat K, Abjean L, Sauvage MC, Haim LB, Escartin C (2016) The complex STATes of astrocyte reactivity: how are they controlled by the JAK–STAT3 pathway? Neuroscience 330:205–218
Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R et al (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532(7598):195–200. https://doi.org/10.1038/nature17623
Kanemaru K, Kubota J, Sekiya H, Hirose K, Okubo Y, Iino M (2013) Calcium-dependent N-cadherin up-regulation mediates reactive astrogliosis and neuroprotection after brain injury. Proc Natl Acad Sci U S A 110(28):11612–11617. https://doi.org/10.1073/pnas.1300378110
Robel S, Mori T, Zoubaa S, Schlegel J, Sirko S, Faissner A et al (2009) Conditional deletion of beta1-integrin in astroglia causes partial reactive gliosis. Glia 57(15):1630–1647. https://doi.org/10.1002/glia.20876
Vakalopoulos C (2017) Alzheimer’s disease: the alternative serotonergic hypothesis of cognitive decline. J Alzheimers Dis 60(3):859–866. https://doi.org/10.3233/JAD-170364
McGeer PL, McGeer EG (2002) Local neuroinflammation and the progression of Alzheimer’s disease. J Neurovirol 8(6):529–538. https://doi.org/10.1080/13550280290100969
Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25(5):663–674. https://doi.org/10.1016/j.neurobiolaging.2004.01.007
Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT et al (2011) Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 8(1):67–80. https://doi.org/10.2174/156720511794604543
Acosta C, Anderson HD, Anderson CM (2017) Astrocyte dysfunction in Alzheimer disease. J Neurosci Res 95(12):2430–2447. https://doi.org/10.1002/jnr.24075
Vincent AJ, Gasperini R, Foa L, Small DH (2010) Astrocytes in Alzheimer’s disease: emerging roles in calcium dysregulation and synaptic plasticity. J Alzheimers Dis 22(3):699–714. https://doi.org/10.3233/JAD-2010-101089
Cassano T, Serviddio G, Gaetani S, Romano A, Dipasquale P, Cianci S et al (2012) Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease. Neurobiol Aging 33(6):1121.e1–1121.12. https://doi.org/10.1016/j.neurobiolaging.2011.09.021
Masliah E, Alford M, Mallory M, Rockenstein E, Moechars D, Van Leuven F (2000) Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice. Exp Neurol 163(2):381–387. https://doi.org/10.1006/exnr.2000.7386
Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ et al (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13(5):584–591. https://doi.org/10.1038/nn.2535
Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH et al (2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 20(8):886–896
Cole SL, Vassar R (2007) The Alzheimer’s disease beta-secretase enzyme, BACE1. Mol Neurodegener 2:22. https://doi.org/10.1186/1750-1326-2-22
Thal DR, Schultz C, Dehghani F, Yamaguchi H, Braak H, Braak E (2000) Amyloid beta-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex. Acta Neuropathol 100(6):608–617. https://doi.org/10.1007/s004010000242
Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J et al (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10(7):719–726. https://doi.org/10.1038/nm1058
Basak JM, Verghese PB, Yoon H, Kim J, Holtzman DM (2012) Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Abeta uptake and degradation by astrocytes. J Biol Chem 287(17):13959–13971. https://doi.org/10.1074/jbc.M111.288746
Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V et al (2009) Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron 64(5):632–644. https://doi.org/10.1016/j.neuron.2009.11.013
Weggen S, Diehlmann A, Buslei R, Beyreuther K, Bayer TA (1998) Prominent expression of presenilin-1 in senile plaques and reactive astrocytes in Alzheimer’s disease brain. Neuroreport 9(14):3279–3283
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4(147)
Garwood C, Faizullabhoy A, Wharton SB, Ince PG, Heath PR, Shaw PJ et al (2013) Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol 39(7):788–799. https://doi.org/10.1111/nan.12033
Kobayashi K, Hayashi M, Nakano H, Fukutani Y, Sasaki K, Shimazaki M et al (2002) Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer’s disease. Neuropathol Appl Neurobiol 28(3):238–251. https://doi.org/10.1046/j.1365-2990.2002.00390.x
Sjobeck M, Englund E (2003) Glial levels determine severity of white matter disease in Alzheimer’s disease: a neuropathological study of glial changes. Neuropathol Appl Neurobiol 29(2):159–169. https://doi.org/10.1046/j.1365-2990.2003.00456.x
Panmontojo F, Anichtchik O, Dening Y, Knels L, Pursche S, Jung R et al 2010 Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One 5(1)
Wang HL, Chou AH, Wu AS, Chen SY, Weng YH, Kao YC et al (2011) PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons. Biochim Biophys Acta 1812(6):674–684. https://doi.org/10.1016/j.bbadis.2011.03.007
Ciesielska A, Joniec I, Kurkowska-Jastrzebska I, Cudna A, Przybylkowski A, Czlonkowska A et al (2009) The impact of age and gender on the striatal astrocytes activation in murine model of Parkinson’s disease. Inflamm Res 58(11):747–753. https://doi.org/10.1007/s00011-009-0026-6
Sriram K, Benkovic SA, Hebert MA, Miller DB, O’Callaghan JP (2004) Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J Biol Chem 279(19):19936–19947. https://doi.org/10.1074/jbc.M309304200
Song YJ, Halliday GM, Holton JL, Lashley T, O’Sullivan SS, McCann H et al (2009) Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol 68(10):1073–1083. https://doi.org/10.1097/NEN.0b013e3181b66f1b
Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 26(1):6–17. https://doi.org/10.1002/mds.23455
Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S et al (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285(12):9262–9272. https://doi.org/10.1074/jbc.M109.081125
Barcia C, Ros CM, Annese V, Gomez A, Ros-Bernal F, Aguado-Llera D et al (2012) IFN-gamma signaling, with the synergistic contribution of TNF-alpha, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis 3:e379. https://doi.org/10.1038/cddis.2012.123
L’Episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC et al (2011) A Wnt1 regulated Frizzled-1/β-cateninsignaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection. Mol Neurodegener 6(1):49. https://doi.org/10.1186/1750-1326-6-49
Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR et al (2015) Huntington disease. Nat Rev Dis Primers 1:15005. https://doi.org/10.1038/nrdp.2015.5
Walker FO (2007) Huntington’s disease. Lancet 369(9557):218–228. https://doi.org/10.1016/S0140-6736(07)60111-1
Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G et al (2010) In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington’s disease subjects. Hum Mol Genet 19(15):3053–3067. https://doi.org/10.1093/hmg/ddq212
Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44(6):559–577. https://doi.org/10.1097/00005072-198511000-00003
Behrens PF, Franz P, Woodman B, Lindenberg KS, Landwehrmeyer GB (2002) Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain 125(Pt 8):1908–1922. https://doi.org/10.1093/brain/awf180
Hassel B, Tessler S, Faull RLM, Emson PC (2008) Glutamate uptake is reduced in prefrontal cortex in Huntington’s disease. Neurochem Res 33(2):232–237
Lievens JC, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L et al (2001) Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 8(5):807–821. https://doi.org/10.1006/nbdi.2001.0430
Lee W, Reyes RC, Gottipati MK, Lewis K, Lesort M, Parpura V et al (2013) Enhanced Ca(2+)-dependent glutamate release from astrocytes of the BACHD Huntington’s disease mouse model. Neurobiol Dis 58:192–199. https://doi.org/10.1016/j.nbd.2013.06.002
Khakh BS, Sofroniew MV (2014) Astrocytes and Huntington’s disease. ACS Chem Neurosci 5(7):494–496
Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J, Haustein MD et al (2014) Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat Neurosci 17(5):694–703. https://doi.org/10.1038/nn.3691
Hsiao HY, Chen YC, Chen HM, Tu PH, Chern Y (2013) A critical role of astrocyte-mediated nuclear factor-kappaB-dependent inflammation in Huntington’s disease. Hum Mol Genet 22(9):1826–1842. https://doi.org/10.1093/hmg/ddt036
Hsiao HY, Chen YC, Huang CH, Chen CC, Hsu YH, Chen HM et al (2015) Aberrant astrocytes impair vascular reactivity in Huntington disease. Ann Neurol 78(2):178–192. https://doi.org/10.1002/ana.24428
Bradford J, Shin JY, Roberts M, Wang CE, Sheng G, Li S et al (2010) Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice. J Biol Chem 285(14):10653–10661. https://doi.org/10.1074/jbc.M109.083287
Bradford J, Shin JY, Roberts M, Wang CE, Li XJ, Li S (2009) Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci U S A 106(52):22480–22485. https://doi.org/10.1073/pnas.0911503106
Juopperi TA, Kim WR, Chiang CH, Yu H, Margolis RL, Ross CA et al (2012) Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington’s disease patient cells. Mol Brain 5:17. https://doi.org/10.1186/1756-6606-5-17
Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O et al (2011) Amyotrophic lateral sclerosis. Lancet 377(9769):942–955. https://doi.org/10.1016/S0140-6736(10)61156-7
Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A et al (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29(9):824–828. https://doi.org/10.1038/nbt.1957
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H et al (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615–622. https://doi.org/10.1038/nn1876
Yamanaka K, Chun SJ, Boillee S, Fujimoritonou N, Yamashita H, Gutmann DH et al (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11(3):251–253
Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G et al (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778):1389–1392. https://doi.org/10.1126/science.1123511
Wang L, Sharma K, Grisotti G, Roos RP (2009) The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol Dis 35(2):234–240. https://doi.org/10.1016/j.nbd.2009.05.002
Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW et al (2013) Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16(5):571–579. https://doi.org/10.1038/nn.3357
Ferrer I (2017) Diversity of astroglial responses across human neurodegenerative disorders and brain aging. Brain Pathol 27(5):645–674. https://doi.org/10.1111/bpa.12538
Ferraiuolo L, Higginbottom A, Heath PR, Barber S, Greenald D, Kirby J et al (2011) Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain 134(Pt 9):2627–2641. https://doi.org/10.1093/brain/awr193
Papadeas ST, Kraig SE, O’Banion C, Lepore AC, Maragakis NJ (2011) Astrocytes carrying the superoxide dismutase 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo. Proc Natl Acad Sci U S A 108(43):17803–17808. https://doi.org/10.1073/pnas.1103141108
Pardo AC, Wong V, Benson LM, Dykes M, Tanaka K, Rothstein JD et al (2006) Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1(G93A) mice. Exp Neurol 201(1):120–130. https://doi.org/10.1016/j.expneurol.2006.03.028
Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2(12):679–689. https://doi.org/10.1038/ncpneuro0355
Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S et al (2014) Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A 111(2):829–832. https://doi.org/10.1073/pnas.1314085111
Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW et al (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16(3):675–686. https://doi.org/10.1016/s0896-6273(00)80086-0
Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38(1):73–84. https://doi.org/10.1002/ana.410380114
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE et al (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433(7021):73–77. https://doi.org/10.1038/nature03180
Phatnani H, Guarnieri P, Friedman BA, Carrasco MA, Muratet M, Okeeffe S et al (2013) Intricate interplay between astrocytes and motor neurons in ALS. Proc Natl Acad Sci U S A 110(8):201222361
Hashioka S, Klegeris A, Schwab C, McGeer PL (2009) Interferon-gamma-dependent cytotoxic activation of human astrocytes and astrocytoma cells. Neurobiol Aging 30(12):1924–1935. https://doi.org/10.1016/j.neurobiolaging.2008.02.019
Hashioka S, Klegeris A, Qing H, McGeer PL (2011) STAT3 inhibitors attenuate interferon-gamma-induced neurotoxicity and inflammatory molecule production by human astrocytes. Neurobiol Dis 41(2):299–307. https://doi.org/10.1016/j.nbd.2010.09.018
Shibata N, Yamamoto T, Hiroi A, Omi Y, Kato Y, Kobayashi M (2010) Activation of STAT3 and inhibitory effects of pioglitazone on STAT3 activity in a mouse model of SOD1-mutated amyotrophic lateral sclerosis. Neuropathology 30(4):353–360. https://doi.org/10.1111/j.1440-1789.2009.01078.x
Martorana F, Brambilla L, Valori CF, Bergamaschi C, Roncoroni C, Aronica E et al (2012) The BH4 domain of Bcl-X L rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals. Hum Mol Genet 21(4):826–840
McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85(3):890–902. https://doi.org/10.1083/jcb.85.3.890
Foo LC, Allen NJ, Bushong EA, Ventura PB, Chung WS, Zhou L et al (2011) Development of a method for the purification and culture of rodent astrocytes. Neuron 71(5):799–811. https://doi.org/10.1016/j.neuron.2011.07.022
Haas R, Werner J, Fliedner TM (1970) Cytokinetics of neonatal brain cell development in rats as studied by the ‘complete 3H-thymidine labelling’ method. J Anat 107:421–437
Skoff RP, Knapp PE (1991) Division of astroblasts and oligodendroblasts in postnatal rodent brain: evidence for separate astrocyte and oligodendrocyte lineages. Glia 4(2):165–174. https://doi.org/10.1002/glia.440040208
Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A et al (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120(3):421–433
Eroglu Ç, Allen NJ, Susman MW, O’Rourke NA, Park CY, Özkan E et al (2009) Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139(2):380–392. https://doi.org/10.1016/j.cell.2009.09.025
Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ et al (2012) Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486(7403):410–414. https://doi.org/10.1038/nature11059
Puschmann TB, Zanden C, Lebkuechner I, Philippot C, de Pablo Y, Liu J et al (2014) HB-EGF affects astrocyte morphology, proliferation, differentiation, and the expression of intermediate filament proteins. J Neurochem 128(6):878–889. https://doi.org/10.1111/jnc.12519
Puschmann TB, de Pablo Y, Zanden C, Liu J, Pekny M (2014) A novel method for three-dimensional culture of central nervous system neurons. Tissue Eng Part C Methods 20(6):485–492. https://doi.org/10.1089/ten.TEC.2013.0445
Puschmann TB, Zanden C, De Pablo Y, Kirchhoff F, Pekna M, Liu J et al (2013) Bioactive 3D cell culture system minimizes cellular stress and maintains the in vivo-like morphological complexity of astroglial cells. Glia 61(3):432–440. https://doi.org/10.1002/glia.22446
Chiu C, Yao N, Guo JH, Shen C, Lee H, Chiu Y et al (2017) Inhibition of astrocytic activity alleviates sequela in acute stages of intracerebral hemorrhage. Oncotarget 8(55):94850–94861
Wilkinson DJ (2009) Stochastic modelling for quantitative description of heterogeneous biological systems. Nat Rev Genet 10(2):122–133. https://doi.org/10.1038/nrg2509
Sandberg R (2014) Entering the era of single-cell transcriptomics in biology and medicine. Nat Methods 11(1):22–24. https://doi.org/10.1038/nmeth.2764
Picelli S, Faridani OR, Bjorklund AK, Winberg G, Sagasser S, Sandberg R (2014) Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc 9(1):171–181. https://doi.org/10.1038/nprot.2014.006
Zeisel A, Munoz-Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A et al (2015) Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347(6226):1138–1142. https://doi.org/10.1126/science.aaa1934
Darmanis S, Sloan SA, Zhang Y, Enge M, Caneda C, Shuer LM et al (2015) A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci U S A 112(23):7285–7290. https://doi.org/10.1073/pnas.1507125112
Saji H (2017) In vivo molecular imaging. Biol Pharm Bull 40(10):1605–1615. https://doi.org/10.1248/bpb.b17-00505
Anderson CJ, Lewis JS (2017) Current status and future challenges for molecular imaging. Philos Trans A Math Phys Eng Sci 375:2107. https://doi.org/10.1098/rsta.2017.0023
Strafella AP, Bohnen NI, Perlmutter JS, Eidelberg D, Pavese N, Van Eimeren T et al (2017) Molecular imaging to track Parkinson’s disease and atypical parkinsonisms: new imaging frontiers. Mov Disord 32(2):181–192. https://doi.org/10.1002/mds.26907
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Li, J., Qin, S. (2022). Activation of Astrocytes in Neurodegenerative Diseases . In: Peplow, P.V., Martinez, B., Gennarelli, T.A. (eds) Neurodegenerative Diseases Biomarkers. Neuromethods, vol 173. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1712-0_3
Download citation
DOI: https://doi.org/10.1007/978-1-0716-1712-0_3
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-1711-3
Online ISBN: 978-1-0716-1712-0
eBook Packages: Springer Protocols