Astroglial atrophy in Alzheimer’s disease

Abstract

Astrocytes, a class of morphologically and functionally diverse primary homeostatic neuroglia, are key keepers of neural tissue homeostasis and fundamental contributors to brain defence in pathological contexts. Failure of astroglial support and defence facilitate the evolution of neurological diseases, which often results in aberrant synaptic transmission, neurodegeneration and death of neurones. In Alzheimer’s disease (AD), astrocytes undergo complex and multifaceted metamorphoses ranging from atrophy with loss of function to reactive astrogliosis with hypertrophy. Astroglial asthenia underlies reduced homeostatic support and neuroprotection that may account for impaired synaptic transmission and neuronal demise. Reactive astrogliosis which mainly develops in astrocytes associated with senile plaque is prominent at the early to moderate stages of AD manifested by mild cognitive impairment; downregulation of astrogliosis (reflecting astroglial paralysis) is associated with late stages of the disease characterised by severe dementia. Cell-specific therapies aimed at boosting astroglial supportive and defensive capabilities and preventing astroglial paralysis may offer new directions in preventing, arresting, or even curing AD-linked neurodegeneration.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Anderson MA, Burda JE, Ren Y, Ao Y, O'Shea TM, Kawaguchi R, Coppola G, Khakh BS, Deming TJ, Sofroniew MV (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200. https://doi.org/10.1038/nature17623

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Andriezen WL (1893) The neuroglia elements of the brain. Br Med J 2:227–230

    CAS  Article  Google Scholar 

  3. 3.

    Arranz AM, De Strooper B (2019) The role of astroglia in Alzheimer’s disease: pathophysiology and clinical implications. Lancet Neurol 18:406–414. https://doi.org/10.1016/S1474-4422(18)30490-3

    CAS  Article  Google Scholar 

  4. 4.

    Barbeito L (2018) Astrocyte-based cell therapy: new hope for amyotrophic lateral sclerosis patients? Stem Cell Res Ther 9:241. https://doi.org/10.1186/s13287-018-1006-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Bartlett TE, Bannister NJ, Collett VJ, Dargan SL, Massey PV, Bortolotto ZA, Fitzjohn SM, Bashir ZI, Collingridge GL, Lodge D (2007) Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. Neuropharmacology 52:60–70. https://doi.org/10.1016/j.neuropharm.2006.07.013

    CAS  Article  Google Scholar 

  6. 6.

    Beach TG, McGeer EG (1988) Lamina-specific arrangement of astrocytic gliosis and senile plaques in Alzheimer’s disease visual cortex. Brain Res 463:357–361

    CAS  Article  Google Scholar 

  7. 7.

    Beauquis J, Pavia P, Pomilio C, Vinuesa A, Podlutskaya N, Galvan V, Saravia F (2013) Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer’s disease. Exp Neurol 239:28–37. https://doi.org/10.1016/j.expneurol.2012.09.009

    CAS  Article  Google Scholar 

  8. 8.

    Beauquis J, Vinuesa A, Pomilio C, Pavia P, Galvan V, Saravia F (2014) Neuronal and glial alterations, increased anxiety, and cognitive impairment before hippocampal amyloid deposition in PDAPP mice, model of Alzheimer’s disease. Hippocampus 24:257–269. https://doi.org/10.1002/hipo.22219

    CAS  Article  Google Scholar 

  9. 9.

    Bedner P, Dupper A, Huttmann K, Muller J, Herde MK, Dublin P, Deshpande T, Schramm J, Haussler U, Haas CA, Henneberger C, Theis M, Steinhauser C (2015) Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain 138:1208–1222. https://doi.org/10.1093/brain/awv067

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Bilkei-Gorzo A (2014) Genetic mouse models of brain ageing and Alzheimer’s disease. Pharmacol Ther 142:244–257. https://doi.org/10.1016/j.pharmthera.2013.12.009

    CAS  Article  Google Scholar 

  11. 11.

    Blocq P, Marinesco G (1892) Sur les lesions et la pathogenie de l’epilepsie dite essentielle. Sem Med 12:445–446

    Google Scholar 

  12. 12.

    Boison D, Chen JF, Fredholm BB (2010) Adenosine signaling and function in glial cells. Cell Death Differ 17:1071–1082. https://doi.org/10.1038/cdd.2009.131

    CAS  Article  Google Scholar 

  13. 13.

    Bonzano S, Crisci I, Podlesny-Drabiniok A, Rolando C, Krezel W, Studer M, De Marchis S (2018) Neuron-astroglia cell fate decision in the adult mouse hippocampal neurogenic niche is cell-intrinsically controlled by COUP-TFI in vivo. Cell Rep 24:329–341. https://doi.org/10.1016/j.celrep.2018.06.044

    CAS  Article  Google Scholar 

  14. 14.

    Bozzali M, Padovani A, Caltagirone C, Borroni B (2011) Regional grey matter loss and brain disconnection across Alzheimer disease evolution. Curr Med Chem 18:2452–2458

    CAS  Article  Google Scholar 

  15. 15.

    Broe M, Kril J, Halliday GM (2004) Astrocytic degeneration relates to the severity of disease in frontotemporal dementia. Brain 127:2214–2220

    Article  Google Scholar 

  16. 16.

    Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81:229–248. https://doi.org/10.1016/j.neuron.2013.12.034

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Burda JE, Sofroniew MV (2017) Seducing astrocytes to the dark side. Cell Res 27:726–727. https://doi.org/10.1038/cr.2017.37

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Burda JE, Bernstein AM, Sofroniew MV (2016) Astrocyte roles in traumatic brain injury. Exp Neurol 275(Pt 3):305–315. https://doi.org/10.1016/j.expneurol.2015.03.020

    CAS  Article  Google Scholar 

  19. 19.

    Busche MA, Grienberger C, Keskin AD, Song B, Neumann U, Staufenbiel M, Forstl H, Konnerth A (2015) Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer's models. Nat Neurosci 18:1725–1727. https://doi.org/10.1038/nn.4163

    CAS  Article  Google Scholar 

  20. 20.

    Bushong EA, Martone ME, Jones YZ, Ellisman MH (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22:183–192

    CAS  Article  Google Scholar 

  21. 21.

    Caiazzo M, Giannelli S, Valente P, Lignani G, Carissimo A, Sessa A, Colasante G, Bartolomeo R, Massimino L, Ferroni S, Settembre C, Benfenati F, Broccoli V (2015) Direct conversion of fibroblasts into functional astrocytes by defined transcription factors. Stem Cell Rep 4:25–36. https://doi.org/10.1016/j.stemcr.2014.12.002

    CAS  Article  Google Scholar 

  22. 22.

    Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, Nordberg A (2012) Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53:37–46. https://doi.org/10.2967/jnumed.110.087031

    CAS  Article  Google Scholar 

  23. 23.

    Castellani RJ, Smith MA (2011) Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is ‘too big to fail’. J Pathol 224:147–152. https://doi.org/10.1002/path.2885

    CAS  Article  Google Scholar 

  24. 24.

    Cheung G, Sibille J, Zapata J, Rouach N (2015) Activity-dependent plasticity of astroglial potassium and glutamate clearance. Neural Plast 2015:109106. https://doi.org/10.1155/2015/109106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Coleman P, Federoff H, Kurlan R (2004) A focus on the synapse for neuroprotection in Alzheimer disease and other dementias. Neurology 63:1155–1162

    Article  Google Scholar 

  26. 26.

    Contini D, Price SD, Art JJ (2017) Accumulation of K+ in the synaptic cleft modulates activity by influencing both vestibular hair cell and calyx afferent in the turtle. J Physiol 595:777–803. https://doi.org/10.1113/JP273060

    CAS  Article  Google Scholar 

  27. 27.

    Cui Z, Feng R, Jacobs S, Duan Y, Wang H, Cao X, Tsien JZ (2013) Increased NR2A:NR2B ratio compresses long-term depression range and constrains long-term memory. Sci Rep 3:1036. https://doi.org/10.1038/srep01036

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Czeh B, Di Benedetto B (2013) Antidepressants act directly on astrocytes: evidences and functional consequences. Eur Neuropsychopharmacol 23:171–185. https://doi.org/10.1016/j.euroneuro.2012.04.017

    CAS  Article  Google Scholar 

  29. 29.

    Czeh B, Nagy SA (2018) Clinical findings documenting cellular and molecular abnormalities of glia in depressive disorders. Front Mol Neurosci 11:56. https://doi.org/10.3389/fnmol.2018.00056

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    De Keyser J, Mostert JP, Koch MW (2008) Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. J Neurol Sci 267:3–16. https://doi.org/10.1016/j.jns.2007.08.044

    CAS  Article  Google Scholar 

  31. 31.

    DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464. https://doi.org/10.1002/ana.410270502

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Diniz LP, Tortelli V, Matias I, Morgado J, Bergamo Araujo AP, Melo HM, Seixas da Silva GS, Alves-Leon SV, de Souza JM, Ferreira ST, De Felice FG, Gomes FCA (2017) Astrocyte transforming growth factor β1 protects synapses against Abeta oligomers in Alzheimer’s disease model. J Neurosci 37:6797–6809. https://doi.org/10.1523/JNEUROSCI.3351-16.2017

    CAS  Article  Google Scholar 

  33. 33.

    Eroglu C, Barres BA (2010) Regulation of synaptic connectivity by glia. Nature 468:223–231. https://doi.org/10.1038/nature09612

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Escartin C, Guillemaud O, Carrillo-de Sauvage M-A (2019) Questions and (some) answers on reactive astrocytes. Glia. https://doi.org/10.1002/glia.23687

  35. 35.

    Estrada-Sánchez AM, Rebec GV (2012) Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington’s disease: interactions between neurons and astrocytes. Basal Ganglia 2:57–66

    Article  Google Scholar 

  36. 36.

    Falk S, Gotz M (2017) Glial control of neurogenesis. Curr Opin Neurobiol 47:188–195. https://doi.org/10.1016/j.conb.2017.10.025

    CAS  Article  Google Scholar 

  37. 37.

    Ferrer I (2017) Diversity of astroglial responses across human neurodegenerative disorders and brain aging. Brain Pathol 27:645–674. https://doi.org/10.1111/bpa.12538

    CAS  Article  Google Scholar 

  38. 38.

    Filosa JA, Morrison HW, Iddings JA, Du W, Kim KJ (2016) Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone. Neuroscience 323:96–109. https://doi.org/10.1016/j.neuroscience.2015.03.064

    CAS  Article  Google Scholar 

  39. 39.

    Fischer O (1907) Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz. Monatsschr Psychiatr Neurol 22:361–372

    Article  Google Scholar 

  40. 40.

    Fischer O (1910) Die presbyofrene Demenz, deren anatomischen Grundlage und klinische Abgrenzung. Z Ges Neurol Psychiatr 3:371–471

    Article  Google Scholar 

  41. 41.

    Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, MacGregor R (1997) Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging 18:431–435

    CAS  Article  Google Scholar 

  42. 42.

    Frazzini V, Guarnieri S, Bomba M, Navarra R, Morabito C, Mariggio MA, Sensi SL (2016) Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer’s disease mouse model. Cell Death Dis 7:e2100. https://doi.org/10.1038/cddis.2016.18

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Garaschuk O, Verkhratsky A (2019) GABAergic astrocytes in Alzheimer’s disease. Aging (Albany NY) 11:1602–1604. https://doi.org/10.18632/aging.101870

    Article  Google Scholar 

  44. 44.

    Gavrilov N, Golyagina I, Brazhe A, Scimemi A, Turlapov V, Semyanov A (2018) Astrocytic coverage of dendritic spines, dendritic shafts, and axonal boutons in hippocampal neuropil. Front Cell Neurosci 12:248. https://doi.org/10.3389/fncel.2018.00248

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Giaume C, Liu X (2012) From a glial syncytium to a more restricted and specific glial networking. J Physiol Paris 106:34–39. https://doi.org/10.1016/j.jphysparis.2011.09.001

    Article  Google Scholar 

  46. 46.

    Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A (2007) Glia: the fulcrum of brain diseases. Cell Death Differ 14:1324–1335. https://doi.org/10.1038/sj.cdd.4402144

    CAS  Article  Google Scholar 

  47. 47.

    Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N (2010) Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci 11:87–99. https://doi.org/10.1038/nrn2757

    CAS  Article  Google Scholar 

  48. 48.

    Ginhoux F, Garel S (2018) The mysterious origins of microglia. Nat Neurosci 21:897–899. https://doi.org/10.1038/s41593-018-0176-3

    CAS  Article  Google Scholar 

  49. 49.

    Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 86:7611–7615

    CAS  Article  Google Scholar 

  50. 50.

    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394. https://doi.org/10.1038/nn1997

    CAS  Article  Google Scholar 

  51. 51.

    Hazell AS (2009) Astrocytes are a major target in thiamine deficiency and Wernicke’s encephalopathy. Neurochem Int 55:129–135

    CAS  Article  Google Scholar 

  52. 52.

    Hazell AS, Sheedy D, Oanea R, Aghourian M, Sun S, Jung JY, Wang D, Wang C (2009) Loss of astrocytic glutamate transporters in Wernicke encephalopathy. Glia 58:148–156

    Article  Google Scholar 

  53. 53.

    Herrup K (2010) Reimagining Alzheimer’s disease--an age-based hypothesis. J Neurosci 30:16755–16762. https://doi.org/10.1523/JNEUROSCI.4521-10.2010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci 27:735–743. https://doi.org/10.1016/j.tins.2004.10.008

    CAS  Article  Google Scholar 

  55. 55.

    Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148:1204–1222. https://doi.org/10.1016/j.cell.2012.02.040

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360. https://doi.org/10.1038/nrn1387

    CAS  Article  Google Scholar 

  57. 57.

    Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376. https://doi.org/10.1038/nn2003

    CAS  Article  Google Scholar 

  58. 58.

    Iram T, Trudler D, Kain D, Kanner S, Galron R, Vassar R, Barzilai A, Blinder P, Fishelson Z, Frenkel D (2016) Astrocytes from old Alzheimer’s disease mice are impaired in Abeta uptake and in neuroprotection. Neurobiol Dis 96:84–94. https://doi.org/10.1016/j.nbd.2016.08.001

    CAS  Article  Google Scholar 

  59. 59.

    Johnson KA, Fox NC, Sperling RA, Klunk WE (2012) Brain imaging in Alzheimer disease. Cold Spring Harb Perspect Med 2:a006213. https://doi.org/10.1101/cshperspect.a006213

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Jones VC, Atkinson-Dell R, Verkhratsky A, Mohamet L (2017) Aberrant iPSC-derived human astrocytes in Alzheimer’s disease. Cell Death Dis 8:e2696. https://doi.org/10.1038/cddis.2017.89

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Kametani F, Hasegawa M (2018) Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’ disease. Front Neurosci 12:25. https://doi.org/10.3389/fnins.2018.00025

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Kamphuis W, Kooijman L, Orre M, Stassen O, Pekny M, Hol EM (2015) GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease. Glia 63:1036–1056. https://doi.org/10.1002/glia.22800

    Article  Google Scholar 

  63. 63.

    Katzman R (1976) Editorial: the prevalence and malignancy of Alzheimer disease. A major killer. Arch Neurol 33:217–218

    CAS  Article  Google Scholar 

  64. 64.

    Kazim SF, Chuang SC, Zhao W, Wong RK, Bianchi R, Iqbal K (2017) Early-onset network hyperexcitability in presymptomatic Alzheimer’s disease transgenic mice is suppressed by passive immunization with anti-human APP/Abeta antibody and by mGluR5 blockade. Front Aging Neurosci 9:71. https://doi.org/10.3389/fnagi.2017.00071

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Kersaitis C, Halliday GM, Kril JJ (2004) Regional and cellular pathology in frontotemporal dementia: relationship to stage of disease in cases with and without pick bodies. Acta Neuropathol 108:515–523

    Article  Google Scholar 

  66. 66.

    Kettenmann H, Ransom BR (eds) (2013) Neuroglia. Oxford University Press, Oxford

    Google Scholar 

  67. 67.

    Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553. https://doi.org/10.1152/physrev.00011.2010

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  68. 68.

    Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18:942–952. https://doi.org/10.1038/nn.4043

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Kimelberg HK, Nedergaard M (2010) Functions of astrocytes and their potential as therapeutic targets. Neurotherapeutics 7:338–353. https://doi.org/10.1016/j.nurt.2010.07.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Koffie RM, Hyman BT, Spires-Jones TL (2011) Alzheimer’s disease: synapses gone cold. Mol Neurodegener 6:63. https://doi.org/10.1186/1750-1326-6-63

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H, Cairns NJ, Crary JF, Duyckaerts C, Ghetti B, Halliday GM, Ironside JW, Love S, Mackenzie IR, Munoz DG, Murray ME, Nelson PT, Takahashi H, Trojanowski JQ, Ansorge O, Arzberger T, Baborie A, Beach TG, Bieniek KF, Bigio EH, Bodi I, Dugger BN, Feany M, Gelpi E, Gentleman SM, Giaccone G, Hatanpaa KJ, Heale R, Hof PR, Hofer M, Hortobagyi T, Jellinger K, Jicha GA, Ince P, Kofler J, Kovari E, Kril JJ, Mann DM, Matej R, AC MK, McLean C, Milenkovic I, Montine TJ, Murayama S, Lee EB, Rahimi J, Rodriguez RD, Rozemuller A, Schneider JA, Schultz C, Seeley W, Seilhean D, Smith C, Tagliavini F, Takao M, Thal DR, Toledo JB, Tolnay M, Troncoso JC, Vinters HV, Weis S, Wharton SB, White CL 3rd, Wisniewski T, Woulfe JM, Yamada M, Dickson DW (2016) Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 131:87–102. https://doi.org/10.1007/s00401-015-1509-x

    CAS  Article  Google Scholar 

  72. 72.

    Kraft AW, Hu X, Yoon H, Yan P, Xiao Q, Wang Y, Gil SC, Brown J, Wilhelmsson U, Restivo JL, Cirrito JR, Holtzman DM, Kim J, Pekny M, Lee JM (2013) Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J 27:187–198. https://doi.org/10.1096/fj.12-208660

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Kulijewicz-Nawrot M, Verkhratsky A, Chvatal A, Sykova E, Rodriguez JJ (2012) Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J Anat 221:252–262. https://doi.org/10.1111/j.1469-7580.2012.01536.x

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Lanciotti A, Brignone MS, Bertini E, Petrucci TC, Aloisi F, Ambrosini E (2013) Astrocytes: emerging stars in leukodystrophy pathogenesis. Transl Neurosci 4. https://doi.org/10.2478/s13380-013-0118-1

  75. 75.

    Lebedeva A, Plata A, Nosova O, Tyurikova O, Semyanov A (2018) Activity-dependent changes in transporter and potassium currents in hippocampal astrocytes. Brain Res Bull 136:37–43. https://doi.org/10.1016/j.brainresbull.2017.08.015

    CAS  Article  Google Scholar 

  76. 76.

    Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.org/10.1038/nature21029

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH (2018) APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98:1141–1154 e1147. https://doi.org/10.1016/j.neuron.2018.05.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Liu CY, Yang Y, Ju WN, Wang X, Zhang HL (2018) Emerging roles of astrocytes in neuro-vascular unit and the tripartite synapse with emphasis on reactive gliosis in the context of Alzheimer’s disease. Front Cell Neurosci 12:193. https://doi.org/10.3389/fncel.2018.00193

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Ma B, Buckalew R, Du Y, Kiyoshi CM, Alford CC, Wang W, McTigue DM, Enyeart JJ, Terman D, Zhou M (2016) Gap junction coupling confers isopotentiality on astrocyte syncytium. Glia 64:214–226. https://doi.org/10.1002/glia.22924

    Article  Google Scholar 

  80. 80.

    Magistretti PJ, Allaman I (2018) Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19:235–249. https://doi.org/10.1038/nrn.2018.19

    CAS  Article  Google Scholar 

  81. 81.

    Meda L, Baron P, Scarlato G (2001) Glial activation in Alzheimer’s disease: the role of Abeta and its associated proteins. Neurobiol Aging 22:885–893

    CAS  Article  Google Scholar 

  82. 82.

    Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE (2012) Alexander disease. J Neurosci 32:5017–5023. https://doi.org/10.1523/JNEUROSCI.5384-11.2012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Miguel-Hidalgo JJ, Waltzer R, Whittom AA, Austin MC, Rajkowska G, Stockmeier CA (2010) Glial and glutamatergic markers in depression, alcoholism, and their comorbidity. J Affect Disord 127:230–240. https://doi.org/10.1016/j.jad.2010.06.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fulop L, Penke B, Zilberter Y, Harkany T, Pitkanen A, Tanila H (2009) Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci 29:3453–3462. https://doi.org/10.1523/JNEUROSCI.5215-08.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Mohamet L, Jones VC, Dayanithi G, Verkhratsky A (2018) Pathological human astroglia in Alzheimer’s disease: opening new horizons with stem cell technology. Future Neurol 13:87–99. https://doi.org/10.2217/fnl-2017-0029

    CAS  Article  Google Scholar 

  86. 86.

    Morizawa YM, Hirayama Y, Ohno N, Shibata S, Shigetomi E, Sui Y, Nabekura J, Sato K, Okajima F, Takebayashi H, Okano H, Koizumi S (2017) Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. Nat Commun 8:28. https://doi.org/10.1038/s41467-017-00037-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Morris GP, Clark IA, Vissel B (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun 2:135. https://doi.org/10.1186/s40478-014-0135-5

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Mrak RE, Griffin WS (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349–354

    CAS  Article  Google Scholar 

  89. 89.

    Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2:a006338

    Article  Google Scholar 

  90. 90.

    Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431:195–199. https://doi.org/10.1038/nature02827

    CAS  Article  Google Scholar 

  91. 91.

    Nagai J, Rajbhandari AK, Gangwani MR, Hachisuka A, Coppola G, Masmanidis SC, Fanselow MS, Khakh BS (2019) Hyperactivity with disrupted attention by activation of an astrocyte synaptogenic cue. Cell 177:1280–1292 e1220. https://doi.org/10.1016/j.cell.2019.03.019

    CAS  Article  Google Scholar 

  92. 92.

    Nagy C, Torres-Platas SG, Mechawar N, Turecki G (2017) Repression of astrocytic connexins in cortical and subcortical brain regions and prefrontal enrichment of H3K9me3 in depression and suicide. Int J Neuropsychopharmacol 20:50–57. https://doi.org/10.1093/ijnp/pyw071

    Article  Google Scholar 

  93. 93.

    Naskar S, Chattarji S (2019) Stress elicits contrasting effects on the structure and number of astrocytes in the amygdala versus hippocampus. eNeuro 6:e0338. https://doi.org/10.1523/ENEURO.0338-18.2019

    CAS  Article  Google Scholar 

  94. 94.

    Nedergaard M, Verkhratsky A (2012) Artifact versus reality--how astrocytes contribute to synaptic events. Glia 60:1013–1023. https://doi.org/10.1002/glia.22288

    Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530

    CAS  Article  Google Scholar 

  96. 96.

    Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen S, Gubert Olive M, Shakirzyanova A, Leskela S, Sarajarvi T, Viitanen M, Rinne JO, Hiltunen M, Haapasalo A, Giniatullin R, Tavi P, Zhang SC, Kanninen KM, Hamalainen RH, Koistinaho J (2017) PSEN1 mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer’s disease. Stem Cell Rep 9:1885–1897. https://doi.org/10.1016/j.stemcr.2017.10.016

    CAS  Article  Google Scholar 

  97. 97.

    Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58:831–838. https://doi.org/10.1002/glia.20967

    Article  Google Scholar 

  98. 98.

    Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2011) Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer’s disease mouse model: mechanism for deficient glutamatergic transmission? Mol Neurodegener 6:55. https://doi.org/10.1186/1750-1326-6-55

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Osborn LM, Kamphuis W, Wadman WJ, Hol EM (2016) Astrogliosis: an integral player in the pathogenesis of Alzheimer’s disease. Prog Neurobiol 144:121–141. https://doi.org/10.1016/j.pneurobio.2016.01.001

    CAS  Article  Google Scholar 

  100. 100.

    Park J, Wetzel I, Marriott I, Dreau D, D'Avanzo C, Kim DY, Tanzi RE, Cho H (2018) A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci 21:941–951. https://doi.org/10.1038/s41593-018-0175-4

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  101. 101.

    Patrushev I, Gavrilov N, Turlapov V, Semyanov A (2013) Subcellular location of astrocytic calcium stores favors extrasynaptic neuron-astrocyte communication. Cell Calcium 54:343–349. https://doi.org/10.1016/j.ceca.2013.08.003

    CAS  Article  Google Scholar 

  102. 102.

    Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94:1077–1098. https://doi.org/10.1152/physrev.00041.2013

    Article  PubMed  Google Scholar 

  103. 103.

    Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V, Hol EM, Sofroniew MV, Verkhratsky A (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345. https://doi.org/10.1007/s00401-015-1513-1

    CAS  Article  Google Scholar 

  104. 104.

    Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32:1152–1166. https://doi.org/10.1038/jcbfm.2011.149

    CAS  Article  Google Scholar 

  105. 105.

    Perez-Alvarez A, Navarrete M, Covelo A, Martin ED, Araque A (2014) Structural and functional plasticity of astrocyte processes and dendritic spine interactions. J Neurosci 34:12738–12744. https://doi.org/10.1523/JNEUROSCI.2401-14.2014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Plata A, Lebedeva A, Denisov P, Nosova O, Postnikova TY, Pimashkin A, Brazhe A, Zaitsev AV, Rusakov DA, Semyanov A (2018) Astrocytic atrophy following status epilepticus parallels reduced Ca2+ activity and impaired synaptic plasticity in the rat hippocampus. Front Mol Neurosci 11:215. https://doi.org/10.3389/fnmol.2018.00215

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Polis B, Srikanth KD, Elliott E, Gil-Henn H, Samson AO (2018) L-Norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease. Neurotherapeutics 15:1036–1054. https://doi.org/10.1007/s13311-018-0669-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Rajkowska G, Miguel-Hidalgo JJ (2007) Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 6:219–233

    CAS  Article  Google Scholar 

  109. 109.

    Rajkowska G, Stockmeier CA (2013) Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 14:1225–1236

    CAS  Article  Google Scholar 

  110. 110.

    Rajkowska G, Legutko B, Moulana M, Syed M, Romero DG, Stockmeier CA, Miguel-Hidalgo JJ (2018) Astrocyte pathology in the ventral prefrontal white matter in depression. J Psychiatr Res 102:150–158. https://doi.org/10.1016/j.jpsychires.2018.04.005

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Reichenbach A, Pannicke T (2008) Neuroscience. A new glance at glia. Science 322:693–694. https://doi.org/10.1126/science.1166197

    CAS  Article  Google Scholar 

  112. 112.

    Rodriguez JJ, Terzieva S, Olabarria M, Lanza RG, Verkhratsky A (2013) Enriched environment and physical activity reverse astrogliodegeneration in the hippocampus of AD transgenic mice. Cell Death Dis 4:e678. https://doi.org/10.1038/cddis.2013.194

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Rossi D (2015) Astrocyte physiopathology: at the crossroads of intercellular networking, inflammation and cell death. Prog Neurobiol 130:86–120. https://doi.org/10.1016/j.pneurobio.2015.04.003

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Rossi D, Volterra A (2009) Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res Bull 80:224–232

    CAS  Article  Google Scholar 

  115. 115.

    Rossi D, Brambilla L, Valori CF, Roncoroni C, Crugnola A, Yokota T, Bredesen DE, Volterra A (2008) Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell Death Differ 15:1691–1700

    CAS  Article  Google Scholar 

  116. 116.

    Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322:1551–1555. https://doi.org/10.1126/science.1164022

    CAS  Article  Google Scholar 

  117. 117.

    Rowland HA, Hooper NM, Kellett KAB (2018) Modelling sporadic Alzheimer’s disease using induced pluripotent stem cells. Neurochem Res 43:2179–2198. https://doi.org/10.1007/s11064-018-2663-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780–786. https://doi.org/10.1038/nature05291

    CAS  Article  PubMed  Google Scholar 

  119. 119.

    Sanacora G, Banasr M (2013) From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry 73:1172–1179. https://doi.org/10.1016/j.biopsych.2013.03.032

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Schwarcz R, Hunter CA (2007) Toxoplasma gondii and schizophrenia: linkage through astrocyte-derived kynurenic acid? Schizophr Bull 33:652–653. https://doi.org/10.1093/schbul/sbm030

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Scofield MD, Li H, Siemsen BM, Healey KL, Tran PK, Woronoff N, Boger HA, Kalivas PW, Reissner KJ (2016) Cocaine self-administration and extinction leads to reduced glial fibrillary acidic protein expression and morphometric features of astrocytes in the nucleus accumbens core. Biol Psychiatry 80:207–215. https://doi.org/10.1016/j.biopsych.2015.12.022

    CAS  Article  Google Scholar 

  122. 122.

    Selkoe D, Mandelkow E, Holtzman D (2012) Deciphering Alzheimer disease. Cold Spring Harb Perspect Med 2:a011460. https://doi.org/10.1101/cshperspect.a011460

    Article  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Semyanov A (2019) Spatiotemporal pattern of calcium activity in astrocytic network. Cell Calcium 78:15–25. https://doi.org/10.1016/j.ceca.2018.12.007

    CAS  Article  Google Scholar 

  124. 124.

    Shih PY, Savtchenko LP, Kamasawa N, Dembitskaya Y, McHugh TJ, Rusakov DA, Shigemoto R, Semyanov A (2013) Retrograde synaptic signaling mediated by K+ efflux through postsynaptic NMDA receptors. Cell Rep 5:941–951. https://doi.org/10.1016/j.celrep.2013.10.026

    CAS  Article  Google Scholar 

  125. 125.

    Shokri-Kojori E, Wang GJ, Wiers CE, Demiral SB, Guo M, Kim SW, Lindgren E, Ramirez V, Zehra A, Freeman C, Miller G, Manza P, Srivastava T, De Santi S, Tomasi D, Benveniste H, Volkow ND (2018) β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A 115:4483–4488. https://doi.org/10.1073/pnas.1721694115

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Simon MJ, Wang MX, Murchison CF, Roese NE, Boespflug EL, Woltjer RL, Iliff JJ (2018) Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology. Sci Rep 8:12389. https://doi.org/10.1038/s41598-018-30779-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. https://doi.org/10.1016/j.tins.2009.08.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Sofroniew MV (2014) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420. https://doi.org/10.1101/cshperspect.a020420

    CAS  Article  PubMed  Google Scholar 

  129. 129.

    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. https://doi.org/10.1007/s00401-009-0619-8

    Article  PubMed  Google Scholar 

  130. 130.

    Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV (2019) Blood-brain barrier: from physiology to disease and back. Physiol Rev 99:21–78. https://doi.org/10.1152/physrev.00050.2017

    CAS  Article  Google Scholar 

  131. 131.

    Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267. https://doi.org/10.1038/nn1623

    CAS  Article  Google Scholar 

  132. 132.

    Tanaka M, Shih PY, Gomi H, Yoshida T, Nakai J, Ando R, Furuichi T, Mikoshiba K, Semyanov A, Itohara S (2013) Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol Brain 6:6. https://doi.org/10.1186/1756-6606-6-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A (2017) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 94:52–58. https://doi.org/10.1016/j.exger.2016.11.004

    CAS  Article  Google Scholar 

  134. 134.

    Terry RD (2000) Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol 59:1118–1119

    CAS  Article  Google Scholar 

  135. 135.

    Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. https://doi.org/10.1002/ana.410300410

    CAS  Article  Google Scholar 

  136. 136.

    Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J, Haustein MD, Anderson MA, Mody I, Olsen ML, Sofroniew MV, Khakh BS (2014) Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat Neurosci 17:694–703. https://doi.org/10.1038/nn.3691

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Valori CF, Guidotti G, Brambilla L, Rossi D (2019) Astrocytes: emerging therapeutic targets in neurological disorders. Trends Mol Med. https://doi.org/10.1016/j.molmed.2019.04.010

  138. 138.

    Valtcheva S, Venance L (2019) Control of long-term plasticity by glutamate transporters. Front Synaptic Neurosci 11:10. https://doi.org/10.3389/fnsyn.2019.00010

    Article  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Verkhratsky A, Butt AM (2013) Glial physiology and pathophysiology. Wiley-Blackwell, Chichester

    Google Scholar 

  140. 140.

    Verkhratsky A, Butt AM (2018) The history of the decline and fall of the glial numbers legend. Neuroglia 1:188–192. https://doi.org/10.3390/neuroglia1010013

    Article  Google Scholar 

  141. 141.

    Verkhratsky A, Nedergaard M (2014) Astroglial cradle in the life of the synapse. Philos Trans R Soc Lond Ser B Biol Sci 369:20130595. https://doi.org/10.1098/rstb.2013.0595

    CAS  Article  Google Scholar 

  142. 142.

    Verkhratsky A, Nedergaard M (2016) The homeostatic astroglia emerges from evolutionary specialization of neural cells. Philos Trans R Soc Lond Ser B Biol Sci 371. https://doi.org/10.1098/rstb.2015.0428

  143. 143.

    Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev 98:239–389. https://doi.org/10.1152/physrev.00042.2016

    CAS  Article  Google Scholar 

  144. 144.

    Verkhratsky A, Parpura V (2016) Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol Dis 85:254–261. https://doi.org/10.1016/j.nbd.2015.03.025

    Article  Google Scholar 

  145. 145.

    Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7:399–412. https://doi.org/10.1016/j.nurt.2010.05.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Verkhratsky A, Parpura V, Rodriguez JJ (2011) Where the thoughts dwell: the physiology of neuronal-glial “diffuse neural net”. Brain Res Rev 66:133–151. https://doi.org/10.1016/j.brainresrev.2010.05.002

    Article  Google Scholar 

  147. 147.

    Verkhratsky A, Rodriguez JJ, Parpura V (2012) Calcium signalling in astroglia. Mol Cell Endocrinol 353:45–56. https://doi.org/10.1016/j.mce.2011.08.039

    CAS  Article  Google Scholar 

  148. 148.

    Verkhratsky A, Sofroniew MV, Messing A, deLanerolle NC, Rempe D, Rodriguez JJ, Nedergaard M (2012) Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 4. https://doi.org/10.1042/AN20120010

  149. 149.

    Verkhratsky A, Rodriguez JJ, Steardo L (2014) Astrogliopathology: a central element of neuropsychiatric diseases? Neuroscientist 20:576–588. https://doi.org/10.1177/1073858413510208

    Article  Google Scholar 

  150. 150.

    Verkhratsky A, Marutle A, Rodriguez-Arellano JJ, Nordberg A (2015) Glial asthenia and functional paralysis: a new perspective on neurodegeneration and Alzheimer’s disease. Neuroscientist 21:552–568. https://doi.org/10.1177/1073858414547132

    CAS  Article  Google Scholar 

  151. 151.

    Verkhratsky A, Zorec R, Rodriguez JJ, Parpura V (2016) Astroglia dynamics in ageing and Alzheimer’s disease. Curr Opin Pharmacol 26:74–79. https://doi.org/10.1016/j.coph.2015.09.011

    CAS  Article  PubMed  Google Scholar 

  152. 152.

    Verkhratsky A, Zorec R, Parpura V (2017) Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27:629–644. https://doi.org/10.1111/bpa.12537

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Virchow R (1860) ). Cellular Pathology. 1st English translation; Robert M De Witt, New York, p. 317 

  154. 154.

    Wakida NM, Cruz GMS, Ro CC, Moncada EG, Khatibzadeh N, Flanagan LA, Berns MW (2018) Phagocytic response of astrocytes to damaged neighboring cells. PLoS One 13:e0196153. https://doi.org/10.1371/journal.pone.0196153

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Wallraff A, Kohling R, Heinemann U, Theis M, Willecke K, Steinhauser C (2006) The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J Neurosci 26:5438–5447. https://doi.org/10.1523/JNEUROSCI.0037-06.2006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Willis T (1672) De Anima Brutorum quae Hominis Vitalis ac Sensitiva est. E Theatro Sheldoniano; Ric.Davis Oxonii (Oxford)

  157. 157.

    Wu Z, Guo Z, Gearing M, Chen G (2014) Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s [corrected] disease model. Nat Commun 5:4159. https://doi.org/10.1038/ncomms5159

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Yamaguchi H, Sugihara S, Ogawa A, Saido TC, Ihara Y (1998) Diffuse plaques associated with astroglial amyloid beta protein, possibly showing a disappearing stage of senile plaques. Acta Neuropathol 95:217–222

    CAS  Article  Google Scholar 

  159. 159.

    Yamanaka K, Komine O (2018) The multi-dimensional roles of astrocytes in ALS. Neurosci Res 126:31–38. https://doi.org/10.1016/j.neures.2017.09.011

    CAS  Article  Google Scholar 

  160. 160.

    Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251–253

    CAS  Article  Google Scholar 

  161. 161.

    Yeh CY, Vadhwana B, Verkhratsky A, Rodriguez JJ (2012) Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro 3:271–279. https://doi.org/10.1042/AN20110025

    CAS  Article  Google Scholar 

  162. 162.

    Yi C, Koulakoff A, Giaume C (2017) Astroglial Connexins as a therapeutic target for Alzheimer’s disease. Curr Pharm Des 23:4958–4968. https://doi.org/10.2174/1381612823666171004151215

    CAS  Article  Google Scholar 

  163. 163.

    Zeidan-Chulia F, Salmina AB, Malinovskaya NA, Noda M, Verkhratsky A, Moreira JC (2014) The glial perspective of autism spectrum disorders. Neurosci Biobehav Rev 38:160–172. https://doi.org/10.1016/j.neubiorev.2013.11.008

    Article  Google Scholar 

  164. 164.

    Zhao Y, Lin Z, Chen L, Ouyang L, Gu L, Chen F, Zhang Q (2018) Hippocampal astrocyte atrophy in a mouse depression model induced by corticosterone is reversed by fluoxetine instead of benzodiazepine diazepam. Prog Neuro-Psychopharmacol Biol Psychiatry 83:99–109. https://doi.org/10.1016/j.pnpbp.2018.01.011

    CAS  Article  Google Scholar 

  165. 165.

    Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50. https://doi.org/10.1038/nn980

    CAS  Article  Google Scholar 

  166. 166.

    Zorec R, Parpura V, Vardjan N, Verkhratsky A (2017) Astrocytic face of Alzheimer’s disease. Behav Brain Res 322:250–257. https://doi.org/10.1016/j.bbr.2016.05.021

    CAS  Article  Google Scholar 

Download references

Funding

AV and AS were supported by Volkswagen Stiftung research grant A115105; RZ by Slovenian Research Agency Research core funding no. P3 310 and projects no. J3 6790, no. J3 9266 and no. J3 7605. AS was supported by COMFI grant 17-00-00412 (K)/17-00-00409 from RFBR and ; AV and AP were supported by the Global Grant measure (No. 09.3.3-LMT-K-712-01-0082).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Alexei Verkhratsky.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Verkhratsky, A., Rodrigues, J.J., Pivoriunas, A. et al. Astroglial atrophy in Alzheimer’s disease. Pflugers Arch - Eur J Physiol 471, 1247–1261 (2019). https://doi.org/10.1007/s00424-019-02310-2

Download citation

Keywords

  • Astrocytes
  • Alzheimer’s disease
  • Astroglial atrophy
  • Astrogliosis
  • Neurological diseases
  • Neurodegeneration