Skip to main content
SpringerLink
Log in

Astroglia in Alzheimer’s Disease

  • Chapter
  • First Online:
Neuroglia in Neurodegenerative Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1175))

Abstract

Alzheimer’s disease is the most common cause of dementia. Cellular changes in the brains of the patients suffering from Alzheimer’s disease occur well in advance of the clinical symptoms. At the cellular level, the most dramatic is a demise of neurones. As astroglial cells carry out homeostatic functions of the brain, it is certain that these cells are at least in part a cause of Alzheimer’s disease. Historically, Alois Alzheimer himself has recognised this at the dawn of the disease description. However, the role of astroglia in this disease has been understudied. In this chapter, we summarise the various aspects of glial contribution to this disease and outline the potential of using these cells in prevention (exercise and environmental enrichment) and intervention of this devastating disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Abdul HM, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, Patel ES, Baig I, Murphy MP, LeVine H 3rd, Kraner SD, Norris CM (2009) Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci 29:12957–12969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abramov AY, Canevari L, Duchen MR (2003) Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J Neurosci 23:5088–5095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Abramov AY, Canevari L, Duchen MR (2004) β-Amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alberdi E, Wyssenbach A, Alberdi M, Sanchez-Gomez MV, Cavaliere F, Rodriguez JJ, Verkhratsky A, Matute C (2013) Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer’s disease. Aging Cell 12:292–302

    Article  CAS  PubMed  Google Scholar 

  5. Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, Magistretti PJ (2010) Amyloid-β aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 30:3326–3338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, Yoshida H, Holzer M, Craxton M, Emson PC, Atzori C, Migheli A, Crowther RA, Ghetti B, Spillantini MG, Goedert M (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22:9340–9351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiat Psych-Gericht Med 64:146–148

    Google Scholar 

  8. Alzheimer A (1910) Beiträge zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgängen im Nervengewebe. In: Nissl F, Alzheimer A (eds) Histologische und histopathologische Arbeiten über die Grosshirnrinde mit besonderer Berücksichtigung der pathologischen Anatomie der Geisteskrankheiten. Jena, Gustav Fischer, pp 401–562

    Google Scholar 

  9. Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590

    Article  CAS  PubMed  Google Scholar 

  10. Aoki C (1992) β-adrenergic receptors: astrocytic localization in the adult visual cortex and their relation to catecholamine axon terminals as revealed by electron microscopic immunocytochemistry. J Neurosci 12:781–792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Apelt J, Ach K, Schliebs R (2003) Aging-related down-regulation of neprilysin, a putative β-amyloid-degrading enzyme, in transgenic Tg2576 Alzheimer-like mouse brain is accompanied by an astroglial upregulation in the vicinity of β-amyloid plaques. Neurosci Lett 339:183–186

    Article  CAS  PubMed  Google Scholar 

  12. Arendash GW, Lewis J, Leighty RE, McGowan E, Cracchiolo JR, Hutton M, Garcia MF (2004) Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer’s disease: linkage of poorer cognitive performance to tau pathology in forebrain. Brain Res 1012:29–41

    Article  CAS  PubMed  Google Scholar 

  13. Arendt T (1994) Impairment in memory function and neurodegenerative changes in the cholinergic basal forebrain system induced by chronic intake of ethanol. J Neural Transm Suppl 44:173–187

    CAS  PubMed  Google Scholar 

  14. Arranz AM, De Strooper B (2019) The role of astroglia in Alzheimer’s disease: pathophysiology and clinical implications. Lancet Neurol 18:406–414

    Article  CAS  PubMed  Google Scholar 

  15. Arranz B, Blennow K, Ekman R, Eriksson A, Mansson JE, Marcusson J (1996) Brain monoaminergic and neuropeptidergic variations in human aging. J Neural Transm (Vienna) 103:101–115

    Article  CAS  Google Scholar 

  16. Ashe KH, Zahs KR (2010) Probing the biology of Alzheimer’s disease in mice. Neuron 66:631–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Barthelemy I, Martineau D, Ong M, Matsunami R, Ling N, Benatti L, Cavallaro U, Soria M, Lappi DA (1993) The expression of saporin, a ribosome-inactivating protein from the plant Saponaria officinalis, in Escherichia coli. J Biol Chem 268:6541–6548

    CAS  PubMed  Google Scholar 

  18. Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. Bekar LK, He W, Nedergaard M (2008) Locus coeruleus α-adrenergic-mediated activation of cortical astrocytes in vivo. Cereb Cortex 18:2789–2795

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bekris LM, Yu CE, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23:213–227

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118:103–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Benarroch EE (2009) The locus ceruleus norepinephrine system: functional organization and potential clinical significance. Neurology 73:1699–1704

    Article  PubMed  Google Scholar 

  26. Berchtold NC, Cotman CW (1998) Evolution in the conceptualization of dementia and Alzheimer’s disease: Greco-Roman period to the 1960s. Neurobiol Aging 19:173–189

    Article  CAS  PubMed  Google Scholar 

  27. Berrios GE (1990) Alzheimer’s disease: A conceptual history. Int J Geriatric Psychiat 5:355–365

    Article  Google Scholar 

  28. Bertoni-Freddari C, Giuli C, Pieri C, Paci D (1986) Quantitative investigation of the morphological plasticity of synaptic junctions in rat dentate gyrus during aging. Brain Res 366:187–192

    Article  CAS  PubMed  Google Scholar 

  29. Biegon A, Greenberger V, Segal M (1986) Quantitative histochemistry of brain acetylcholinesterase and learning rate in the aged rat. Neurobiol Aging 7:215–217

    Article  CAS  PubMed  Google Scholar 

  30. Bielschowsky M (1903) Die Ziele bei Impregnation der Neurofibrillen. Neurol Centralbl 22:997–1006

    Google Scholar 

  31. Bigl M, Bruckner MK, Arendt T, Bigl V, Eschrich K (1999) Activities of key glycolytic enzymes in the brains of patients with Alzheimer’s disease. J Neural Transm 106:499–511

    Article  CAS  PubMed  Google Scholar 

  32. Blanchard V, Moussaoui S, Czech C, Touchet N, Bonici B, Planche M, Canton T, Jedidi I, Gohin M, Wirths O, Bayer TA, Langui D, Duyckaerts C, Tremp G, Pradier L (2003) Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol 184:247–263

    Article  CAS  PubMed  Google Scholar 

  33. Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B (2000) Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1-40 and Abeta1-42 by human astrocytes. Neurobiol Dis 7:682–689

    Article  CAS  PubMed  Google Scholar 

  34. Blass JP, Sheu RK, Gibson GE (2000) Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise. Ann NY Acad Sci 903:204–221

    Article  CAS  PubMed  Google Scholar 

  35. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  37. Boegman RJ, el-Defrawy SR, Jhamandas K, Beninger RJ, Ludwin SK (1985) Quinolinic acid neurotoxicity in the nucleus basalis antagonized by kynurenic acid. Neurobiol Aging 6:331–336

    Google Scholar 

  38. Boller F, Forbes MM (1998) History of dementia and dementia in history: an overview. J Neurol Sci 158:125–133

    Article  CAS  PubMed  Google Scholar 

  39. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  CAS  PubMed  Google Scholar 

  40. Brambilla L, Martorana F, Rossi D (2013) Astrocyte signaling and neurodegeneration: new insights into CNS disorders. Prion 7:28–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Brawek B, Chesters R, Klement D, Muller J, Lerdkrai C, Hermes M, Garaschuk O (2018) A bell-shaped dependence between amyloidosis and GABA accumulation in astrocytes in a mouse model of Alzheimer’s disease. Neurobiol Aging 61:187–197

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  43. Burkovetskaya M, Karpuk N, Xiong J, Bosch M, Boska MD, Takeuchi H, Suzumura A, Kielian T (2014) Evidence for aberrant astrocyte hemichannel activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). PLoS ONE 9:e95023

    Article  PubMed  PubMed Central  Google Scholar 

  44. Carroll JC, Rosario ER, Chang L, Stanczyk FZ, Oddo S, LaFerla FM, Pike CJ (2007) Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci 27:13357–13365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Carter SF, Herholz K, Rosa-Neto P, Pellerin L, Nordberg A, Zimmer ER (2019) Astrocyte biomarkers in Alzheimer’s disease. Trends Mol Med 25:77–95

    Article  CAS  PubMed  Google Scholar 

  46. 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

    Article  CAS  PubMed  Google Scholar 

  47. Casley CS, Lakics V, Lee HG, Broad LM, Day TA, Cluett T, Smith MA, O’Neill MJ, Kingston AE (2009) Up-regulation of astrocyte metabotropic glutamate receptor 5 by amyloid-β peptide. Brain Res

    Google Scholar 

  48. Cassel JC, Mathis C, Majchrzak M, Moreau PH, Dalrymple-Alford JC (2008) Coexisting cholinergic and parahippocampal degeneration: a key to memory loss in dementia and a challenge for transgenic models? Neurodegener Dis 5:304–317

    Article  PubMed  Google Scholar 

  49. Castellani RJ, Lee HG, Siedlak SL, Nunomura A, Hayashi T, Nakamura M, Zhu X, Perry G, Smith MA (2009) Reexamining Alzheimer’s disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis 18:447–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Celsus AC (1935–1938) De Medicina. With an english translation by W. G. Spencer. William Heinemann Ltd., London

    Google Scholar 

  51. Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D (2001) Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276:21562–21570

    Article  CAS  PubMed  Google Scholar 

  52. Chow SK, Yu D, Macdonald CL, Buibas M, Silva GA (2010) Amyloid β-peptide directly induces spontaneous calcium transients, delayed intercellular calcium waves and gliosis in rat cortical astrocytes. ASN Neuro 2:e00026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chrobak JJ, Hanin I, Schmechel DE, Walsh TJ (1988) AF64A-induced working memory impairment: behavioral, neurochemical and histological correlates. Brain Res 463:107–117

    Article  CAS  PubMed  Google Scholar 

  54. Cicero (2003) On old age. In: On the good life, pp 160–194. Folio Society, London

    Google Scholar 

  55. 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  PubMed  Google Scholar 

  56. Contestabile A, Stirpe F (1993) Ribosome-inactivating proteins from plants as agents for suicide transport and immunolesioning in the nervous system. Eur J Neurosci 5:1292–1301

    Article  CAS  PubMed  Google Scholar 

  57. Coradazzi M, Gulino R, Garozzo S, Leanza G (2010) Selective lesion of the developing central noradrenergic system: short- and long-term effects and reinnervation by noradrenergic-rich tissue grafts. J Neurochem 114:761–771

    Article  CAS  PubMed  Google Scholar 

  58. Danbolt NC (2001) Glutamate uptake. Progr Neurobiol 65:1–105

    Article  CAS  Google Scholar 

  59. Daschil N, Geisler S, Obermair GJ, Humpel C (2014) Short- and long-term treatment of mouse cortical primary astrocytes with beta-amyloid differentially regulates the mRNA expression of L-type calcium channels. Pharmacology 93:24–31

    Article  CAS  PubMed  Google Scholar 

  60. Decker MW (1987) The effects of aging on hippocampal and cortical projections of the forebrain cholinergic system. Brain Res 434:423–438

    Article  CAS  PubMed  Google Scholar 

  61. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464

    Article  CAS  PubMed  Google Scholar 

  62. Delekate A, Fuchtemeier M, Schumacher T, Ulbrich C, Foddis M, Petzold GC (2014) Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model. Nat Commun 5:5422

    Article  PubMed  Google Scholar 

  63. Depboylu C, Stricker S, Ghobril JP, Oertel WH, Priller J, Hoglinger GU (2012) Brain-resident microglia predominate over infiltrating myeloid cells in activation, phagocytosis and interaction with T-lymphocytes in the MPTP mouse model of Parkinson disease. Exp Neurol 238:183–191

    Article  CAS  PubMed  Google Scholar 

  64. DeWitt DA, Perry G, Cohen M, Doller C, Silver J (1998) Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer’s disease. Exp Neurol 149:329–340

    Article  CAS  PubMed  Google Scholar 

  65. Di Patre PL, Abbamondi A, Bartolini L, Pepeu G (1989) GM1 ganglioside counteracts cholinergic and behavioral deficits induced in the rat by intracerebral injection of vincristine. Eur J Pharmacol 162:43–50

    Article  PubMed  Google Scholar 

  66. Ding F, O’Donnell J, Thrane AS, Zeppenfeld D, Kang H, Xie L, Wang F, Nedergaard M (2013) α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice. Cell Calcium 54:387–394

    Article  CAS  PubMed  Google Scholar 

  67. Dodart JC, Mathis C, Saura J, Bales KR, Paul SM, Ungerer A (2000) Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic mice. Neurobiol Dis 7:71–85

    Article  CAS  PubMed  Google Scholar 

  68. Dorfman VB, Pasquini L, Riudavets M, Lopez-Costa JJ, Villegas A, Troncoso JC, Lopera F, Castano EM, Morelli L (2010) Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer’s disease. Neurobiol Aging 31:1743–1757

    Article  CAS  PubMed  Google Scholar 

  69. Dunnett SB, Everitt BJ, Robbins TW (1991) The basal forebrain-cortical cholinergic system: interpreting the functional consequences of excitotoxic lesions. Trends Neurosci 14:494–501

    Article  CAS  PubMed  Google Scholar 

  70. Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36

    Article  CAS  PubMed  Google Scholar 

  71. Enkvist MO, Holopainen I, Akerman KE (1989) Glutamate receptor-linked changes in membrane potential and intracellular Ca2+ in primary rat astrocytes. Glia 2:397–402

    Article  CAS  PubMed  Google Scholar 

  72. Eriksen JL, Janus CG (2007) Plaques, tangles, and memory loss in mouse models of neurodegeneration. Behav Genet 37:79–100

    Article  PubMed  Google Scholar 

  73. Eroglu C, Barres BA (2010) Regulation of synaptic connectivity by glia. Nature 468:223–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Farkas E, Luiten PG (2001) Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64:575–611

    Article  CAS  PubMed  Google Scholar 

  75. Feinstein DL, Kalinin S, Braun D (2016) Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system. J Neurochem 139(Suppl 2):154–178

    Article  CAS  PubMed  Google Scholar 

  76. Fiol-deRoque MA, Gutierrez-Lanza R, Torres M, Terés S, Barceló P, Rial RV, Verkhratsky A, Escribá PV, Busquets X, Rodríguez JJ (2013) Cognitive recovery and restoration of cell proliferation in the dentate gyrus in the 5XFAD transgenic mice model of Alzheimer’s disease following 2-hydroxy-DHA treatment. Biogerontology (in press)

    Google Scholar 

  77. Fischer O (1907) Miliäre Nekrosen mit drusigen wucherungen der neurofibrillen, eine regelmässige veränderung der hirnrinde bei seniler demenz. Monatsschr Psychiatr Neurol 22:361–372

    Article  Google Scholar 

  78. Fischer W, Chen KS, Gage FH, Bjorklund A (1992) Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging. Neurobiol Aging 13:9–23

    Article  CAS  PubMed  Google Scholar 

  79. Flood DG, Lin YG, Lang DM, Trusko SP, Hirsch JD, Savage MJ, Scott RW, Howland DS (2009) A transgenic rat model of Alzheimer’s disease with extracellular Aβ deposition. Neurobiol Aging 30:1078–1090

    Article  CAS  PubMed  Google Scholar 

  80. Fontana L, Partridge L, Longo VD (2010) Extending healthy life span–from yeast to humans. Science 328:321–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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

    Article  CAS  PubMed  Google Scholar 

  82. Frost GR, Li YM (2017) The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol 7

    Google Scholar 

  83. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527

    Google Scholar 

  84. Garaschuk O, Verkhratsky A (2019) GABAergic astrocytes in Alzheimer’s disease. Aging (Albany NY) 11:1602–1604

    Article  Google Scholar 

  85. Garwood C, Faizullabhoy A, Wharton SB, Ince PG, Heath PR, Shaw PJ, Baxter L, Gelsthorpe C, Forster G, Matthews FE, Brayne C, Simpson JE (2013) Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol 39:788–799

    Article  CAS  PubMed  Google Scholar 

  86. Gerkau NJ, Kafitz KW, Rose CR (2019) Imaging of local and global sodium signals in astrocytes. Methods Mol Biol 1938:187–202

    Article  PubMed  Google Scholar 

  87. Gerlai R (2001) Alzheimer’s disease: beta-amyloid hypothesis strengthened! Trends Neurosci 24:199

    Article  CAS  PubMed  Google Scholar 

  88. Giovannini MG, Scali C, Prosperi C, Bellucci A, Vannucchi MG, Rosi S, Pepeu G, Casamenti F (2002) Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis 11:257–274

    Article  CAS  PubMed  Google Scholar 

  89. Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301 l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495

    Article  CAS  PubMed  Google Scholar 

  90. Gotz J, Probst A, Spillantini MG, Schafer T, Jakes R, Burki K, Goedert M (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 14:1304–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gotz J, Streffer JR, David D, Schild A, Hoerndli F, Pennanen L, Kurosinski P, Chen F (2004) Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy. Mol Psychiatry 9:664–683

    Article  CAS  PubMed  Google Scholar 

  92. 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 USA 86:7611–7615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Grolla AA, Fakhfouri G, Balzaretti G, Marcello E, Gardoni F, Canonico PL, DiLuca M, Genazzani AA, Lim D (2013) Aβ leads to Ca2+ signaling alterations and transcriptional changes in glial cells. Neurobiol Aging 34:511–522

    Article  CAS  PubMed  Google Scholar 

  94. Grolla AA, Sim JA, Lim D, Rodriguez JJ, Genazzani AA, Verkhratsky A (2013) Amyloid-β and Alzheimer’s disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. Cell Death Dis 4:e623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Grosche J, Matyash V, Moller T, Verkhratsky A, Reichenbach A, Kettenmann H (1999) Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci 2:139–143

    Article  CAS  PubMed  Google Scholar 

  96. Guenette SY (2003) Astrocytes: a cellular player in Aβ clearance and degradation. Trends Mol Med 9:279–280

    Article  CAS  PubMed  Google Scholar 

  97. Hanin I (1996) The AF64A model of cholinergic hypofunction: an update. Life Sci 58:1955–1964

    Article  CAS  PubMed  Google Scholar 

  98. Hardy J (2006) Has the amyloid cascade hypothesis for Alzheimer’s disease been proved? Curr Alzheimer Res 3:71–73

    Article  CAS  PubMed  Google Scholar 

  99. Hardy J (2009) The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem 110:1129–1134

    Article  CAS  PubMed  Google Scholar 

  100. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  101. Hartlage-Rubsamen M, Zeitschel U, Apelt J, Gartner U, Franke H, Stahl T, Gunther A, Schliebs R, Penkowa M, Bigl V, Rossner S (2003) Astrocytic expression of the Alzheimer’s disease β-secretase (BACE1) is stimulus-dependent. Glia 41:169–179

    Article  PubMed  Google Scholar 

  102. Haug H, Eggers R (1991) Morphometry of the human cortex cerebri and corpus striatum during aging. Neurobiol Aging 12:336–338; discussion 352–335

    Google Scholar 

  103. Haughey NJ, Mattson MP (2003) Alzheimer’s amyloid β-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes. Neuromolecular Med 3:173–180

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  105. 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 

  106. Heneka MT, Rodriguez JJ, Verkhratsky A (2010) Neuroglia in neurodegeneration. Brain Res Rev (in press)

    Google Scholar 

  107. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F (2005) Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APPV717I transgenic mice. J Neuroinflam 2:22

    Article  CAS  Google Scholar 

  108. Henry V, Paille V, Lelan F, Brachet P, Damier P (2009) Kinetics of microglial activation and degeneration of dopamine-containing neurons in a rat model of Parkinson disease induced by 6-hydroxydopamine. J Neuropathol Exp Neurol 68:1092–1102

    Article  CAS  PubMed  Google Scholar 

  109. Hodges JR (2006) Alzheimer’s centennial legacy: origins, landmarks and the current status of knowledge concerning cognitive aspects. Brain 129:2811–2822

    Article  PubMed  Google Scholar 

  110. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102

    Article  CAS  PubMed  Google Scholar 

  111. Humphry GM (1889) Old age. Macmillan & Bowes, Cambridge

    Google Scholar 

  112. Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376

    Article  CAS  PubMed  Google Scholar 

  113. Ishihara T, Higuchi M, Zhang B, Yoshiyama Y, Hong M, Trojanowski JQ, Lee VM (2001) Attenuated neurodegenerative disease phenotype in tau transgenic mouse lacking neurofilaments. J Neurosci 21:6026–6035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jalonen TO, Charniga CJ, Wielt DB (1997) β-Amyloid peptide-induced morphological changes coincide with increased K+ and Cl- channel activity in rat cortical astrocytes. Brain Res 746:85–97

    Article  CAS  PubMed  Google Scholar 

  115. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D (2000) A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408:979–982

    Article  CAS  PubMed  Google Scholar 

  116. Jellinger KA (2008) Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia. Neurodegener Dis 5:118–121

    Article  CAS  PubMed  Google Scholar 

  117. Jin SM, Cho HJ, Kim YW, Hwang JY, Mook-Jung I (2012) Abeta-induced Ca(2+) influx regulates astrocytic BACE1 expression via calcineurin/NFAT4 signals. Biochem Biophys Res Commun 425:649–655

    Article  CAS  PubMed  Google Scholar 

  118. Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, Bae JY, Kim T, Lee J, Chun H, Park HJ, Lee DY, Hong J, Kim HY, Oh SJ, Park SJ, Lee H, Yoon BE, Kim Y, Jeong Y, Shim I, Bae YC, Cho J, Kowall NW, Ryu H, Hwang E, Kim D, Lee CJ (2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 20:886–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jones VC, Atkinson-Dell R, Verkhratsky A, Mohamet L (2017) Aberrant iPSC-derived human astrocytes in Alzheimer’s disease. Cell Death Dis 8:e2696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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 USA 110:11612–11617

    Article  PubMed  PubMed Central  Google Scholar 

  121. Karenberg A, Forstl H (2006) Dementia in the Greco-Roman world. J Neurol Sci 244:5–9

    Article  PubMed  Google Scholar 

  122. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712

    Article  CAS  PubMed  Google Scholar 

  123. Kaul M, Lipton SA (2006) Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr HIV Res 4:307–318

    Article  CAS  PubMed  Google Scholar 

  124. 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  PubMed  Google Scholar 

  125. Khachaturian ZS (1987) Hypothesis on the regulation of cytosol calcium concentration and the aging brain. Neurobiol Aging 8:345–346

    Article  CAS  PubMed  Google Scholar 

  126. Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R, Dasgupta S, Barral PM, Hedvat M, Diaz P, Reed JC, Stebbins JL, Pellecchia M, Sarkar D, Fisher PB (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226:2484–2493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kirischuk S, Kettenmann H, Verkhratsky A (1997) Na+/Ca2+ exchanger modulates kainate-triggered Ca2+ signaling in Bergmann glial cells in situ. FASEB J 11:566–572

    Article  CAS  PubMed  Google Scholar 

  128. Kirischuk S, Kettenmann H, Verkhratsky A (2007) Membrane currents and cytoplasmic sodium transients generated by glutamate transport in Bergmann glial cells. Pflugers Arch 454:245–252

    Article  CAS  PubMed  Google Scholar 

  129. Kirischuk S, Moller T, Voitenko N, Kettenmann H, Verkhratsky A (1995) ATP-induced cytoplasmic calcium mobilization in Bergmann glial cells. J Neurosci 15:7861–7871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kirischuk S, Parpura V, Verkhratsky A (2012) Sodium dynamics: another key to astroglial excitability? Trends Neurosci 35:497–506

    Article  CAS  PubMed  Google Scholar 

  131. Kirischuk S, Tuschick S, Verkhratsky A, Kettenmann H (1996) Calcium signalling in mouse Bergmann glial cells mediated by α1-adrenoreceptors and H1 histamine receptors. Eur J Neurosci 8:1198–1208

    Article  CAS  PubMed  Google Scholar 

  132. Kloskowska E, Pham TM, Nilsson T, Zhu S, Oberg J, Codita A, Pedersen LA, Pedersen JT, Malkiewicz K, Winblad B, Folkesson R, Benedikz E (2010) Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer’s disease. J Cell Mol Med 14:1816–1823

    Article  CAS  PubMed  Google Scholar 

  133. Knight RA, Verkhratsky A (2010) Neurodegenerative diseases: failures in brain connectivity? Cell Death Differ 17:1069–1070

    Article  CAS  PubMed  Google Scholar 

  134. Korczyn AD (2008) The amyloid cascade hypothesis. Alzheimers Dement 4:176–178

    Article  CAS  PubMed  Google Scholar 

  135. Korsakoff SS (1889) Кopcaкoв, C.C. Пcиxичecкoe paccтpoйcтвo в coчeтaнии c мнoжecтвeнным нeвpитoм (psychosis polineuritica, s. cerebropathia psychica toxaemica). English translation: Korsakoff SS. Psychic disorder in conjunction with multiple neuritis, Translated from Russian by M. Victor and P. Yakovlev, Neurology (1955), 5:394–406. Meд oбoзp 32:3–18

    Google Scholar 

  136. Kraepelin E (1910) Psychiatrie: Ein Lehrbuch fuer Studierende und Arzte. Johann Ambrosius Barth, Leipzig

    Google Scholar 

  137. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ (2009) Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323:1211–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 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

    Article  PubMed  PubMed Central  Google Scholar 

  140. Kuo MF, Paulus W, Nitsche MA (2014) Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases. Neuroimage 85(Pt 3):948–960

    Article  PubMed  Google Scholar 

  141. Kurumatani T, Fastbom J, Bonkale WL, Bogdanovic N, Winblad B, Ohm TG, Cowburn RF (1998) Loss of inositol 1,4,5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer’s disease neurofibrillary pathology. Brain Res 796:209–221

    Article  CAS  PubMed  Google Scholar 

  142. LaFerla FM, Green KN (2012) Animal models of Alzheimer disease. Cold Spring Harb Perspect Med 2

    Google Scholar 

  143. Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25:11693–11709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lalo U, Palygin O, North RA, Verkhratsky A, Pankratov Y (2011) Age-dependent remodelling of ionotropic signalling in cortical astroglia. Aging Cell 10:392–402

    Article  CAS  PubMed  Google Scholar 

  145. Lalo U, Rasooli-Nejad S, Pankratov Y (2014) Exocytosis of gliotransmitters from cortical astrocytes: implications for synaptic plasticity and aging. Biochem Soc Trans 42:1275–1281

    Article  CAS  PubMed  Google Scholar 

  146. Landfield PW (1987) ‘Increased calcium-current’ hypothesis of brain aging. Neurobiol Aging 8:346–347

    Article  CAS  PubMed  Google Scholar 

  147. Landfield PW, Pitler TA (1984) Prolonged Ca2+ -dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 226:1089–1092

    Article  CAS  PubMed  Google Scholar 

  148. Langer J, Gerkau NJ, Derouiche A, Kleinhans C, Moshrefi-Ravasdjani B, Fredrich M, Kafitz KW, Seifert G, Steinhauser C, Rose CR (2017) Rapid sodium signaling couples glutamate uptake to breakdown of ATP in perivascular astrocyte endfeet. Glia 65:293–308

    Article  PubMed  Google Scholar 

  149. Langer J, Rose CR (2009) Synaptically induced sodium signals in hippocampal astrocytes in situ. J Physiol 587:5859–5877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Langer J, Stephan J, Theis M, Rose CR (2012) Gap junctions mediate intercellular spread of sodium between hippocampal astrocytes in situ. Glia 60:239–252

    Article  PubMed  Google Scholar 

  151. Lappi DA, Esch FS, Barbieri L, Stirpe F, Soria M (1985) Characterization of a Saponaria officinalis seed ribosome-inactivating protein: immunoreactivity and sequence homologies. Biochem Biophys Res Commun 129:934–942

    Article  CAS  PubMed  Google Scholar 

  152. Lazzarini M, Martin S, Mitkovski M, Vozari RR, Stuhmer W, Bel ED (2013) Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model. Glia 61:1084–1100

    Article  PubMed  Google Scholar 

  153. Leanza G, Gulino R, Zorec R (2018) Noradrenergic hypothesis linking neurodegeneration-based cognitive decline and astroglia. Front Mol Neurosci 11:254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Lee L, Kosuri P, Arancio O (2014) Picomolar amyloid-β peptides enhance spontaneous astrocyte calcium transients. J Alzheimers Dis 38:49–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lee M, Schwab C, McGeer PL (2011) Astrocytes are GABAergic cells that modulate microglial activity. Glia 59:152–165

    Article  PubMed  Google Scholar 

  156. Lescaudron L, Stein DG (1999) Differences in memory impairment and response to GM1 ganglioside treatment following electrolytic or ibotenic acid lesions of the nucleus basalis magnocellularis. Restor Neurol Neurosci 15:25–37

    CAS  PubMed  Google Scholar 

  157. Leuba G, Wernli G, Vernay A, Kraftsik R, Mohajeri MH, Saini KD (2005) Neuronal and nonneuronal quantitative BACE immunocytochemical expression in the entorhinohippocampal and frontal regions in Alzheimer’s disease. Dement Geriatr Cogn Disord 19:171–183

    Article  CAS  PubMed  Google Scholar 

  158. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491

    Article  CAS  PubMed  Google Scholar 

  159. Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405

    Article  CAS  PubMed  Google Scholar 

  160. Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A, Niedzielko TL, Schneider LE, Mastroeni D, Caselli R, Kukull W, Morris JC, Hulette CM, Schmechel D, Rogers J, Stephan DA (2008) Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A 105:4441–4446

    Article  PubMed  PubMed Central  Google Scholar 

  161. Lim D, Iyer A, Ronco V, Grolla AA, Canonico PL, Aronica E, Genazzani AA (2013) Amyloid β deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-κB. Glia 61:1134–1145

    Article  PubMed  Google Scholar 

  162. Lim D, Rodriguez-Arellano JJ, Parpura V, Zorec R, Zeidan-Chulia F, Genazzani AA, Verkhratsky A (2016) Calcium signalling toolkits in astrocytes and spatio-temporal progression of Alzheimer’s disease. Curr Alzheimer Res 13:359–369

    Article  CAS  PubMed  Google Scholar 

  163. Lim D, Ronco V, Grolla AA, Verkhratsky A, Genazzani AA (2014) Glial calcium signalling in Alzheimer’s disease. Rev Physiol Biochem Pharmacol 167:45–65

    Article  CAS  PubMed  Google Scholar 

  164. Linde CI, Baryshnikov SG, Mazzocco-Spezzia A, Golovina VA (2011) Dysregulation of Ca2+ signaling in astrocytes from mice lacking amyloid precursor protein. Am J Physiol Cell Physiol 300:C1502–1512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Lyketsos CG, Olin J (2002) Depression in Alzheimer’s disease: overview and treatment. Biol Psychiatry 52:243–252

    Article  PubMed  Google Scholar 

  166. Martins RN, Taddei K, Kendall C, Evin G, Bates KA, Harvey AR (2001) Altered expression of apolipoprotein E, amyloid precursor protein and presenilin-1 is associated with chronic reactive gliosis in rat cortical tissue. Neuroscience 106:557–569

    Article  CAS  PubMed  Google Scholar 

  167. Mather M, Harley CW (2016) The locus coeruleus: essential for maintaining cognitive function and the aging brain. Trends Cogn Sci 20:214–226

    Article  PubMed  PubMed Central  Google Scholar 

  168. Matos M, Augusto E, Oliveira CR, Agostinho P (2008) Amyloid-β peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades. Neuroscience 156:898–910

    Article  CAS  PubMed  Google Scholar 

  169. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM (2017) Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 8:14063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Mattson MP (2012) Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 16:706–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Mattson MP, Haughey NJ, Nath A (2005) Cell death in HIV dementia. Cell Death Differ 12(Suppl 1):893–904

    Article  CAS  PubMed  Google Scholar 

  172. Maurer K, Volk S, Gerbaldo H (1997) Auguste D and Alzheimer’s disease. Lancet 349:1546–1549

    Article  CAS  PubMed  Google Scholar 

  173. Maurya SK, Rai A, Rai NK, Deshpande S, Jain R, Mudiam MK, Prabhakar YS, Bandyopadhyay S (2012) Cypermethrin induces astrocyte apoptosis by the disruption of the autocrine/paracrine mode of epidermal growth factor receptor signaling. Toxicol Sci 125:473–487

    Article  CAS  PubMed  Google Scholar 

  174. McAlpine D, Araki S (1958) Minamata disease: an unusual neurological disorder caused by contaminated fish. Lancet 2:629–631

    Article  CAS  PubMed  Google Scholar 

  175. McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 10:63–79

    Article  CAS  Google Scholar 

  176. McEntee WJ, Crook TH (1991) Serotonin, memory, and the aging brain. Psychopharmacology 103:143–149

    Article  CAS  PubMed  Google Scholar 

  177. McKee AC, Carreras I, Hossain L, Ryu H, Klein WL, Oddo S, LaFerla FM, Jenkins BG, Kowall NW, Dedeoglu A (2008) Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice. Brain Res 1207:225–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 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

    Article  CAS  PubMed  Google Scholar 

  179. Mena MA, Casarejos MJ, Carazo A, Paino CL, Garcia de Yebenes J (1996) Glia conditioned medium protects fetal rat midbrain neurones in culture from L-DOPA toxicity. NeuroReport 7:441–445

    Article  CAS  PubMed  Google Scholar 

  180. Mena MA, de Bernardo S, Casarejos MJ, Canals S, Rodriguez-Martin E (2002) The role of astroglia on the survival of dopamine neurons. Mol Neurobiol 25:245–263

    Article  CAS  PubMed  Google Scholar 

  181. Mena MA, Garcia de Yebenes J (2008) Glial cells as players in parkinsonism: the “good,” the “bad,” and the “mysterious” glia. Neuroscientist 14:544–560

    Article  CAS  PubMed  Google Scholar 

  182. Mesulam M, Shaw P, Mash D, Weintraub S (2004) Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol 55:815–828

    Article  CAS  PubMed  Google Scholar 

  183. Moechars D, Lorent K, De Strooper B, Dewachter I, Van Leuven F (1996) Expression in brain of amyloid precursor protein mutated in the alpha-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice. EMBO J 15:1265–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. 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

    Article  CAS  Google Scholar 

  185. Mohs RC (2005) The clinical syndrome of Alzheimer’s disease: aspects particularly relevant to clinical trials. Genes Brain Behav 4:129–133

    Article  CAS  PubMed  Google Scholar 

  186. Monai H, Ohkura M, Tanaka M, Oe Y, Konno A, Hirai H, Mikoshiba K, Itohara S, Nakai J, Iwai Y, Hirase H (2016) Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain. Nat Commun 7:11100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Mosconi L, Pupi A, De Leon MJ (2008) Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann NY Acad Sci 1147:180–195

    Article  CAS  PubMed  Google Scholar 

  188. Mouton PR, Pakkenberg B, Gundersen HJ, Price DL (1994) Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals. J Chem Neuroanat 7:185–190

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  190. Mravec B, Lejavova K, Cubinkova V (2014) Locus (coeruleus) minoris resistentiae in pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 11:992–1001

    Article  CAS  PubMed  Google Scholar 

  191. Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431:195–199

    Article  CAS  PubMed  Google Scholar 

  192. Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY (2003) Astrocytes accumulate A β 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971:197–209

    Article  CAS  PubMed  Google Scholar 

  193. 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 25:663–674

    Article  CAS  PubMed  Google Scholar 

  194. Ni M, Li X, Rocha JB, Farina M, Aschner M (2012) Glia and methylmercury neurotoxicity. J Toxicol Environ Health A 75:1091–1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Nicoll JA, Weller RO (2003) A new role for astrocytes: β-amyloid homeostasis and degradation. Trends Mol Med 9:281–282

    Article  CAS  PubMed  Google Scholar 

  196. Nimmerjahn A, Mukamel EA, Schnitzer MJ (2009) Motor behavior activates Bergmann glial networks. Neuron 62:400–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, Paulus W, Hummel F, Boggio PS, Fregni F, Pascual-Leone A (2008) Transcranial direct current stimulation: state of the art 2008. Brain Stimul 1:206–223

    Article  PubMed  Google Scholar 

  198. Noristani HN, Olabarria M, Verkhratsky A, Rodriguez JJ (2010) Serotonin fibre sprouting and increase in serotonin transporter immunoreactivity in the CA1 area of hippocampus in a triple transgenic mouse model of Alzheimer’s disease. Eur J Neurosci 32:71–79

    Article  CAS  PubMed  Google Scholar 

  199. Norris CM, Kadish I, Blalock EM, Chen KC, Thibault V, Porter NM, Landfield PW, Kraner SD (2005) Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer’s models. J Neurosci 25:4649–4658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24:1063–1070

    Article  CAS  PubMed  Google Scholar 

  202. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39:409–421

    Article  CAS  PubMed  Google Scholar 

  203. 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

    PubMed  Google Scholar 

  204. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Orre M, Kamphuis W, Osborn LM, Jansen AHP, Kooijman L, Bossers K, Hol EM (2014) Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol Aging 35:2746–2760

    Article  CAS  PubMed  Google Scholar 

  206. Ovsepian SV, O’Leary VB, Zaborszky L, Ntziachristos V, Dolly JO (2018) Amyloid plaques of Alzheimer’s disease as hotspots of glutamatergic activity. Neuroscientist. https://doi.org/10.1177/1073858418791128

  207. Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Pankratov Y, Lalo U (2015) Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex. Front Cell Neurosci 9:230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Parpura-Gill A, Beitz D, Uemura E (1997) The inhibitory effects of beta-amyloid on glutamate and glucose uptakes by cultured astrocytes. Brain Res 754:65–71

    Article  CAS  PubMed  Google Scholar 

  210. Paukert M, Agarwal A, Cha J, Doze VA, Kang JU, Bergles DE (2014) Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82:1263–1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Pavia J, Alberch J, Alvarez I, Toledano A, de Ceballos ML (2000) Repeated intracerebroventricular administration of beta-amyloid(25-35) to rats decreases muscarinic receptors in cerebral cortex. Neurosci Lett 278:69–72

    Article  CAS  PubMed  Google Scholar 

  212. 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

    Article  CAS  PubMed  Google Scholar 

  213. Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32:1152–1166

    Article  CAS  PubMed  Google Scholar 

  214. Pepeu G, Marconcini Pepeu I (1994) Dysfunction of the brain cholinergic system during aging and after lesions of the nucleus basalis of Meynert. J Neural Transm Suppl 44:189–194

    CAS  PubMed  Google Scholar 

  215. Picklo MJ, Wiley RG, Lappi DA, Robertson D (1994) Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin. Brain Res 666:195–200

    Article  CAS  PubMed  Google Scholar 

  216. Pirttimaki TM, Codadu NK, Awni A, Pratik P, Nagel DA, Hill EJ, Dineley KT, Parri HR (2013) α7 Nicotinic receptor-mediated astrocytic gliotransmitter release: Aβ effects in a preclinical Alzheimer’s mouse model. PLoS ONE 8:e81828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Plata A, Popov A, Denisov P, Bychkov M, Brazhe A, Lyukmanova E, Natalia Lazareva N, Verkhratsky A, Semyanov A (2019) An astrocytic basis of caloric restriction action on the brain plasticity. BioRxiv

    Google Scholar 

  218. Potokar M, Kreft M, Pangrsic T, Zorec R (2005) Vesicle mobility studied in cultured astrocytes. Biochem Biophys Res Commun 329:678–683

    Article  CAS  PubMed  Google Scholar 

  219. Potokar M, Stenovec M, Gabrijel M, Li L, Kreft M, Grilc S, Pekny M, Zorec R (2010) Intermediate filaments attenuate stimulation-dependent mobility of endosomes/lysosomes in astrocytes. Glia 58:1208–1219

    Article  PubMed  Google Scholar 

  220. Potokar M, Vardjan N, Stenovec M, Gabrijel M, Trkov S, Jorgacevski J, Kreft M, Zorec R (2013) Astrocytic vesicle mobility in health and disease. Int J Mol Sci 14:11238–11258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Potts R, Leech RW (2005) Thalamic dementia: an example of primary astroglial dystrophy of Seitelberger. Clin Neuropathol 24:271–275

    CAS  PubMed  Google Scholar 

  222. Pressey SN, Smith DA, Wong AM, Platt FM, Cooper JD (2012) Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice. Neurobiol Dis 45:1086–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Rai A, Maurya SK, Sharma R, Ali S (2013) Down-regulated GFAPα: a major player in heavy metal induced astrocyte damage. Toxicol Mech Methods 23:99–107

    Article  CAS  PubMed  Google Scholar 

  224. Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, Guimaraes A, Yue M, Lewis J, Carlson G, Hutton M, Ashe KH (2005) Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25:10637–10647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Redlich E (1898) Ueber miliare Sklerose der Hirnrinde bei seniler Atrophie. J Psychiat Neurol 17:208–216

    Google Scholar 

  226. Reitz C (2012) Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis 2012:369808

    PubMed  PubMed Central  Google Scholar 

  227. Reyes RC, Verkhratsky A, Parpura V (2013) TRPC1-mediated Ca2+ and Na+ signalling in astroglia: differential filtering of extracellular cations. Cell Calcium 54:120–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Ribe EM, Perez M, Puig B, Gich I, Lim F, Cuadrado M, Sesma T, Catena S, Sanchez B, Nieto M, Gomez-Ramos P, Moran MA, Cabodevilla F, Samaranch L, Ortiz L, Perez A, Ferrer I, Avila J, Gomez-Isla T (2005) Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis 20:814–822

    Article  CAS  PubMed  Google Scholar 

  229. Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Scholl M, Chiotis K, Thordardottir S, Graff C, Wall A, Langstrom B, Nordberg A (2016) Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain 139:922–936

    Article  PubMed  PubMed Central  Google Scholar 

  230. Rodriguez JJ, Butt AM, Gardenal E, Parpura V, Verkhratsky A (2016) Complex and differential glial responses in Alzheimer’s disease and ageing. Curr Alzheimer Res 13:343–358

    Article  CAS  PubMed  Google Scholar 

  231. Rodriguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, Oddo S, Verkhratsky A (2008) Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS ONE 3:e2935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Rodríguez JJ, Matute C, Verkhratsky AI (ed)(2011) Neuroglia in Alzheimer’s disease. In: Schemes E, Spray DC (eds) Astrocytes: wiring the brain, pp 311–337. Taylor & Francis Inc

    Google Scholar 

  233. Rodriguez JJ, Noristani HN, Olabarria M, Fletcher J, Somerville TD, Yeh CY, Verkhratsky A (2011) Voluntary running and environmental enrichment restores impaired hippocampal neurogenesis in a triple transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res 8:707–717

    Article  CAS  PubMed  Google Scholar 

  234. Rodriguez JJ, Noristani HN, Verkhratsky A (2012) The serotonergic system in ageing and Alzheimer’s disease. Prog Neurobiol 99:15–41

    Article  CAS  PubMed  Google Scholar 

  235. Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A (2009) Astroglia in dementia and Alzheimer’s disease. Cell Death Differ 16:378–385

    Article  CAS  PubMed  Google Scholar 

  236. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Rodriguez JJ, Verkhratsky A (2011) Neurogenesis in Alzheimer’s disease. J Anat 219:78–89

    Article  PubMed  PubMed Central  Google Scholar 

  238. Rodriguez JJ, Verkhratsky A (2011) Neuroglial roots of neurodegenerative diseases? Mol Neurobiol 43:87–96

    Article  CAS  PubMed  Google Scholar 

  239. Ronco V, Grolla AA, Glasnov TN, Canonico PL, Verkhratsky A, Genazzani AA, Lim D (2014) Differential deregulation of astrocytic calcium signalling by amyloid-β, TNFα, IL-1β and LPS. Cell Calcium 55:219–229

    Article  CAS  PubMed  Google Scholar 

  240. Rose CR, Verkhratsky A (2016) Principles of sodium homeostasis and sodium signalling in astroglia. Glia

    Google Scholar 

  241. 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  243. Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR (2005) Alzheimer’s disease beta-secretase BACE1 is not a neuron-specific enzyme. J Neurochem 92:226–234

    Article  CAS  PubMed  Google Scholar 

  244. Roth M, Tomlinson BE, Blessed G (1966) Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects. Nature 209:109–110

    Article  CAS  PubMed  Google Scholar 

  245. Roth M, Tomlinson BE, Blessed G (1967) The relationship between quantitative measures of dementia and of degenerative changes in the cerebral grey matter of elderly subjects. Proc R Soc Med 60:254–260

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Rusakov DA (2015) Disentangling calcium-driven astrocyte physiology. Nat Rev Neurosci 16:226–233

    Article  CAS  PubMed  Google Scholar 

  247. Samuel W, Masliah E, Hill LR, Butters N, Terry R (1994) Hippocampal connectivity and Alzheimer’s dementia: effects of synapse loss and tangle frequency in a two-component model. Neurology 44:2081–2088

    Article  CAS  PubMed  Google Scholar 

  248. Sani S, Traul D, Klink A, Niaraki N, Gonzalo-Ruiz A, Wu CK, Geula C (2003) Distribution, progression and chemical composition of cortical amyloid-beta deposits in aged rhesus monkeys: similarities to the human. Acta Neuropathol 105:145–156

    CAS  PubMed  Google Scholar 

  249. Satoh A, Iijima KM (2019) Roles of tau pathology in the locus coeruleus (LC) in age-associated pathophysiology and Alzheimer’s disease pathogenesis: potential strategies to protect the LC against aging. Brain Res 1702:17–28

    Article  CAS  PubMed  Google Scholar 

  250. Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F, Markowska AL, Borchelt DR (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18:602–617

    Article  CAS  PubMed  Google Scholar 

  251. Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384

    Article  CAS  PubMed  Google Scholar 

  252. Schindowski K, Bretteville A, Leroy K, Begard S, Brion JP, Hamdane M, Buee L (2006) Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169:599–616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Schousboe A, Wellendorph P, Frolund B, Clausen RP, Krogsgaard-Larsen P (2017) Astrocytic GABA transporters: pharmacological properties and targets for antiepileptic drugs. Adv Neurobiol 16:283–296

    Article  PubMed  Google Scholar 

  254. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    Article  CAS  PubMed  Google Scholar 

  255. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    Article  CAS  PubMed  Google Scholar 

  256. Semyanov A (2019) Spatiotemporal pattern of calcium activity in astrocytic network. Cell Calcium 78:15–25

    Article  CAS  PubMed  Google Scholar 

  257. Shastry BS, Giblin FJ (1999) Genes and susceptible loci of Alzheimer’s disease. Brain Res Bull 48:121–127

    Article  CAS  PubMed  Google Scholar 

  258. Shaughnessy LW, Barone S Jr, Mundy WR, Herr DW, Tilson HA (1994) Comparison of intracranial infusions of colchicine and ibotenic acid as models of neurodegeneration in the basal forebrain. Brain Res 637:15–26

    Article  CAS  PubMed  Google Scholar 

  259. Shigetomi E, Kracun S, Sofroniew MV, Khakh BS (2010) A genetically targeted optical sensor to monitor calcium signals in astrocyte processes. Nat Neurosci 13:759–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Sidoryk-Wegrzynowicz M, Aschner M (2013) Role of astrocytes in manganese mediated neurotoxicity. BMC Pharmacol Toxicol 14:23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F, Savva G, Brayne C, Wharton SB (2010) Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 31:578–590

    Article  CAS  PubMed  Google Scholar 

  262. Simpson JE, Ince PG, Shaw PJ, Heath PR, Raman R, Garwood CJ, Gelsthorpe C, Baxter L, Forster G, Matthews FE, Brayne C, Wharton SB (2011) Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol Aging 32:1795–1807

    Article  CAS  PubMed  Google Scholar 

  263. Son SM, Cha MY, Choi H, Kang S, Choi H, Lee MS, Park SA, Mook-Jung I (2016) Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease. Autophagy 12:784–800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Soucek T, Cumming R, Dargusch R, Maher P, Schubert D (2003) The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Neuron 39:43–56

    Article  CAS  PubMed  Google Scholar 

  265. Srinivasan R, Huang BS, Venugopal S, Johnston AD, Chai H, Zeng H, Golshani P, Khakh BS (2015) Ca2+ signaling in astrocytes from Ip3r2-/- mice in brain slices and during startle responses in vivo. Nat Neurosci 18:708–717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Stenovec M, Kreft M, Grilc S, Pangrsic T, Zorec R (2008) EAAT2 density at the astrocyte plasma membrane and Ca2+-regulated exocytosis. Mol Membr Biol 25:203–215

    Article  CAS  PubMed  Google Scholar 

  267. Stenovec M, Lasic E, Dominkus PP, Bobnar ST, Zorec R, Lenassi M, Kreft M (2019) Slow release of HIV-1 protein nef from vesicle-like structures is inhibited by cytosolic calcium elevation in single human microglia. Mol Neurobiol 56:102–118

    Article  CAS  PubMed  Google Scholar 

  268. Stenovec M, Trkov Bobnar S, Smolic T, Kreft M, Parpura V, Zorec R (2018) Presenilin PS1E9 disrupts mobility of secretory organelles in rat astrocytes. Acta Physiol (Oxf) 223:e13046

    Article  CAS  Google Scholar 

  269. Stenovec M, Trkov S, Lasic E, Terzieva S, Kreft M, Rodriguez Arellano JJ, Parpura V, Verkhratsky A, Zorec R (2016) Expression of familial Alzheimer disease presenilin 1 gene attenuates vesicle traffic and reduces peptide secretion in cultured astrocytes devoid of pathologic tissue environment. Glia 64:317–329

    Article  PubMed  Google Scholar 

  270. Stix B, Reiser G (1998) β-amyloid peptide 25–35 regulates basal and hormone-stimulated Ca2+ levels in cultured rat astrocytes. Neurosci Lett 243:121–124

    Article  CAS  PubMed  Google Scholar 

  271. Studelska DR, Brimijoin S (1989) Partial isolation of two classes of dopamine beta-hydroxylase-containing particles undergoing rapid axonal transport in rat sciatic nerve. J Neurochem 53:622–631

    Article  CAS  PubMed  Google Scholar 

  272. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94:13287–13292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Stutzmann GE (2007) The pathogenesis of Alzheimers disease is it a lifelong “calciumopathy”? Neuroscientist 13:546–559

    Article  CAS  PubMed  Google Scholar 

  274. Stutzmann GE, Mattson MP (2011) Endoplasmic reticulum Ca2+ handling in excitable cells in health and disease. Pharmacol Rev 63:700–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Suarez-Fernandez MB, Soldado AB, Sanz-Medel A, Vega JA, Novelli A, Fernandez-Sanchez MT (1999) Aluminum-induced degeneration of astrocytes occurs via apoptosis and results in neuronal death. Brain Res 835:125–136

    Article  CAS  PubMed  Google Scholar 

  276. Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, Harrington MG, Pa J, Law M, Wang DJJ, Jacobs RE, Doubal FN, Ramirez J, Black SE, Nedergaard M, Benveniste H, Dichgans M, Iadecola C, Love S, Bath PM, Markus HS, Salman RA, Allan SM, Quinn TJ, Kalaria RN, Werring DJ, Carare RO, Touyz RM, Williams SCR, Moskowitz MA, Katusic ZS, Lutz SE, Lazarov O, Minshall RD, Rehman J, Davis TP, Wellington CL, Gonzalez HM, Yuan C, Lockhart SN, Hughes TM, Chen CLH, Sachdev P, O’Brien JT, Skoog I, Pantoni L, Gustafson DR, Biessels GJ, Wallin A, Smith EE, Mok V, Wong A, Passmore P, Barkof F, Muller M, Breteler MMB, Roman GC, Hamel E, Seshadri S, Gottesman RF, van Buchem MA, Arvanitakis Z, Schneider JA, Drewes LR, Hachinski V, Finch CE, Toga AW, Wardlaw JM, Zlokovic BV (2019) Vascular dysfunction-The disregarded partner of Alzheimer’s disease. Alzheimers Dement 15:158–167

    Article  PubMed  PubMed Central  Google Scholar 

  277. 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

    Article  CAS  PubMed  Google Scholar 

  278. Takano T, Han X, Deane R, Zlokovic B, Nedergaard M (2007) Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease. Ann N Y Acad Sci 1097:40–50

    Article  CAS  PubMed  Google Scholar 

  279. 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

    Article  CAS  PubMed  Google Scholar 

  280. Tanemura K, Murayama M, Akagi T, Hashikawa T, Tominaga T, Ichikawa M, Yamaguchi H, Takashima A (2002) Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci 22:133–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Tatebayashi Y, Miyasaka T, Chui DH, Akagi T, Mishima K, Iwasaki K, Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sato S, Hashikawa T, Takashima A (2002) Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad Sci USA 99:13896–13901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  283. Thompson KA, McArthur JC, Wesselingh SL (2001) Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia. Ann Neurol 49:745–752

    Article  CAS  PubMed  Google Scholar 

  284. Thompson PM, Hayashi KM, de Zubicaray G, Janke AL, Rose SE, Semple J, Herman D, Hong MS, Dittmer SS, Doddrell DM, Toga AW (2003) Dynamics of gray matter loss in Alzheimer’s disease. J Neurosci 23:994–1005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Thompson PM, Hayashi KM, Dutton RA, Chiang MC, Leow AD, Sowell ER, De Zubicaray G, Becker JT, Lopez OL, Aizenstein HJ, Toga AW (2007) Tracking Alzheimer’s disease. Ann NY Acad Sci 1097:183–214

    Article  PubMed  Google Scholar 

  286. Toescu EC, Verkhratsky A (2007) The importance of being subtle: small changes in calcium homeostasis control cognitive decline in normal aging. Aging Cell 6:267–273

    Article  CAS  PubMed  Google Scholar 

  287. Toescu EC, Verkhratsky A, Landfield PW (2004) Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci 27:614–620

    Article  CAS  PubMed  Google Scholar 

  288. Toivari E, Manninen T, Nahata AK, Jalonen TO, Linne ML (2011) Effects of transmitters and amyloid-beta peptide on calcium signals in rat cortical astrocytes: Fura-2AM measurements and stochastic model simulations. PLoS ONE 6:e17914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Toledano A, Alvarez MI (2004) Lesions and dysfunctions of the nucleus basalis as Alzheimer’s disease models: general and critical overview and analysis of the long-term changes in several excitotoxic models. Curr Alzheimer Res 189–214

    Google Scholar 

  290. Tomlinson BE, Blessed G, Roth M (1970) Observations on the brains of demented old people. J Neurol Sci 11:205–242

    Article  CAS  PubMed  Google Scholar 

  291. Torack R (1996) The early history of senile dementia. In: Reisberg B (ed) Alzheimer’s disease: the standard reference. The Free Press, New York, pp 23–28

    Google Scholar 

  292. Ullian EM, Christopherson KS, Barres BA (2004) Role for glia in synaptogenesis. Glia 47:209–216

    Article  PubMed  Google Scholar 

  293. Vale-Martinez A, Guillazo-Blanch G, Marti-Nicolovius M, Nadal R, Arevalo-Garcia R, Morgado-Bernal I (2002) Electrolytic and ibotenic acid lesions of the nucleus basalis magnocellularis interrupt long-term retention, but not acquisition of two-way active avoidance, in rats. Exp Brain Res 142:52–66

    Article  PubMed  Google Scholar 

  294. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K (2016) The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med 18:421–430

    Article  PubMed  Google Scholar 

  295. Vanzani MC, Iacono RF, Caccuri RL, Troncoso AR, Berria MI (2006) Regional differences in astrocyte activation in HIV-associated dementia. Medicina (B Aires) 66:108–112

    Google Scholar 

  296. Vardjan N, Gabrijel M, Potokar M, Svajger U, Kreft M, Jeras M, de Pablo Y, Faiz M, Pekny M, Zorec R (2012) IFN-γ-induced increase in the mobility of MHC class II compartments in astrocytes depends on intermediate filaments. J Neuroinflammation 9:144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Vardjan N, Kreft M, Zorec R (2014) Dynamics of β-adrenergic/cAMP signaling and morphological changes in cultured astrocytes. Glia 62:566–579

    Article  PubMed  Google Scholar 

  298. Vardjan N, Verkhratsky A, Zorec R (2015) Pathologic potential of astrocytic vesicle traffic: new targets to treat neurologic diseases? Cell Transplant 24:599–612

    Article  PubMed  Google Scholar 

  299. Verkhratsky A, Kettenmann H (1996) Calcium signalling in glial cells. Trends Neurosci 19:346–352

    Article  CAS  PubMed  Google Scholar 

  300. 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

    Article  CAS  PubMed  Google Scholar 

  301. Verkhratsky A, Matteoli M, Parpura V, Mothet JP, Zorec R (2016) Astrocytes as secretory cells of the central nervous system: idiosyncrasies of vesicular secretion. EMBO J 35:239–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Verkhratsky A, Mattson MP, Toescu EC (2004) Aging in the mind. Trends Neurosci 27:577–578

    Article  CAS  PubMed  Google Scholar 

  303. Verkhratsky A, Nedergaard M (2014) Astroglial cradle in the life of the synapse. Philos Trans R Soc Lond B Biol Sci 369:20130595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Verkhratsky A, Nedergaard M (2016) The homeostatic astroglia emerges from evolutionary specialization of neural cells. Philos Trans R Soc Lond B Biol Sci 371

    Google Scholar 

  305. Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev 98:239–389

    Article  CAS  PubMed  Google Scholar 

  306. Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7:399–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  307. Verkhratsky A, Parpura V (2016) Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol Dis 85:254–261

    Article  PubMed  Google Scholar 

  308. Verkhratsky A, Parpura V, Rodriguez JJ (2014) Neurodegeneration and neuroglia: emphasis on astroglia in Alzheimer’s disease. In: Parpura V, Verkhratsky A (eds) Pathological potential of neuroglia: possible new targets for medical intervention. Springer, Heidelberg, pp 264–291

    Google Scholar 

  309. Verkhratsky A, Rodriguez-Arellano JJ, Parpura V, Zorec R (2017) Astroglial calcium signalling in Alzheimer’s disease. Biochem Biophys Res Commun 483:1005–1012

    Article  CAS  PubMed  Google Scholar 

  310. Verkhratsky A, Rodriguez JJ, Parpura V (2013) Astroglia in neurological diseases. Future Neurol 8:149–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  311. 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

    Google Scholar 

  312. Verkhratsky A, Toescu EC (1998) Calcium and neuronal ageing. Trends Neurosci 21:2–7

    Article  CAS  PubMed  Google Scholar 

  313. Verkhratsky A, Trebak M, Perocchi F, Khananshvili D, Sekler I (2018) Crosslink between calcium and sodium signalling. Exp Physiol 103:157–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  314. Verkhratsky A, Untiet V, Rose CR (2019) Ionic signalling in astroglia beyond calcium. J Physiol

    Google Scholar 

  315. Verkhratsky A, Zorec R, Parpura V (2017) Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27:629–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  316. Verkhratsky A, Zorec R, Rodriguez JJ, Parpura V (2016) Astroglia dynamics in ageing and Alzheimer’s disease. Curr Opin Pharmacol 26:74–79

    Article  CAS  PubMed  Google Scholar 

  317. Verkhratsky A, Zorec R, Rodriguez JJ, Parpura V (2017) Neuroglia: functional paralysis and reactivity in Alzheimer’s disease and other neurodegenerative pathologies. Adv Neurobiol 15:427–449

    Article  PubMed  Google Scholar 

  318. Waite JJ, Chen AD, Wardlow ML, Wiley RG, Lappi DA, Thal LJ (1995) 192 immunoglobulin G-saporin produces graded behavioral and biochemical changes accompanying the loss of cholinergic neurons of the basal forebrain and cerebellar Purkinje cells. Neuroscience 65:463–476

    Article  CAS  PubMed  Google Scholar 

  319. Walls AB, Waagepetersen HS, Bak LK, Schousboe A, Sonnewald U (2015) The glutamine-glutamate/GABA cycle: function, regional differences in glutamate and GABA production and effects of interference with GABA metabolism. Neurochem Res 40:402–409

    Article  CAS  PubMed  Google Scholar 

  320. Weidenheim KM, Dickson DW, Rapin I (2009) Neuropathology of Cockayne syndrome: evidence for impaired development, premature aging, and neurodegeneration. Mech Ageing Dev 130:619–636

    Article  CAS  PubMed  Google Scholar 

  321. Weinshilboum RM (1978) Serum dopamine beta-hydroxylase. Pharmacol Rev 30:133–166

    CAS  PubMed  Google Scholar 

  322. Wellman CL, Pelleymounter MA (1999) Differential effects of nucleus basalis lesions in young adult and aging rats. Neurobiol Aging 20:381–393

    Article  CAS  PubMed  Google Scholar 

  323. Wernicke C (1881–1883) Lehrbuch der Gehirnkrankheiten für Aerzte und Studirende. Theodor Fischer, Kassel und Berlin

    Google Scholar 

  324. Wharton SB, O’Callaghan JP, Savva GM, Nicoll JA, Matthews F, Simpson JE, Forster G, Shaw PJ, Brayne C, Ince PG (2009) Population variation in glial fibrillary acidic protein levels in brain ageing: relationship to Alzheimer-type pathology and dementia. Dement Geriatr Cogn Disord 27:465–473

    Article  CAS  PubMed  Google Scholar 

  325. Wiley RG (1992) Neural lesioning with ribosome-inactivating proteins: suicide transport and immunolesioning. Trends Neurosci 15:285–290

    Article  CAS  PubMed  Google Scholar 

  326. Wiley RG, Kline IR (2000) Neuronal lesioning with axonally transported toxins. J Neurosci Methods 103:73–82

    Article  CAS  PubMed  Google Scholar 

  327. Wiley RG, Oeltmann TN, Lappi DA (1991) Immunolesioning: selective destruction of neurons using immunotoxin to rat NGF receptor. Brain Res 562:149–153

    Article  CAS  PubMed  Google Scholar 

  328. Wilson CS, Mongin AA (2019) The signaling role for chloride in the bidirectional communication between neurons and astrocytes. Neurosci Lett 689:33–44

    Article  CAS  PubMed  Google Scholar 

  329. Wilson RS, Nag S, Boyle PA, Hizel LP, Yu L, Buchman AS, Schneider JA, Bennett DA (2013) Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology 80:1202–1208

    Article  PubMed  PubMed Central  Google Scholar 

  330. Winkler J, Thal LJ (1995) Effects of nerve growth factor treatment on rats with lesions of the nucleus basalis magnocellularis produced by ibotenic acid, quisqualic acid, and AMPA. Exp Neurol 136:234–250

    Article  CAS  PubMed  Google Scholar 

  331. Wrenn CC, Picklo MJ, Lappi DA, Robertson D, Wiley RG (1996) Central noradrenergic lesioning using anti-DBH-saporin: anatomical findings. Brain Res 740:175–184

    Article  CAS  PubMed  Google Scholar 

  332. 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

    Article  CAS  PubMed  Google Scholar 

  333. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat Med 9:453–457

    Article  CAS  PubMed  Google Scholar 

  334. Xiong J, Verkhratsky A, Toescu EC (2002) Changes in mitochondrial status associated with altered Ca2+ homeostasis in aged cerebellar granule neurons in brain slices. J Neurosci 22:10761–10771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  335. Xiu J, Nordberg A, Zhang JT, Guan ZZ (2005) Expression of nicotinic receptors on primary cultures of rat astrocytes and up-regulation of the α7, α4 and β2 subunits in response to nanomolar concentrations of the β-amyloid peptide1-42. Neurochem Int 47:281–290

    Article  CAS  PubMed  Google Scholar 

  336. 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

    Article  CAS  PubMed  Google Scholar 

  337. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  338. Yeh CY, Vadhwana B, Verkhratsky A, Rodriguez JJ (2011) Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro 3:271–279

    Article  CAS  PubMed  Google Scholar 

  339. Yin Z, Milatovic D, Aschner JL, Syversen T, Rocha JB, Souza DO, Sidoryk M, Albrecht J, Aschner M (2007) Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes. Brain Res 1131:1–10

    Article  CAS  PubMed  Google Scholar 

  340. Young LT, Kish SJ, Li PP, Warsh JJ (1988) Decreased brain [3H]inositol 1,4,5-trisphosphate binding in Alzheimer’s disease. Neurosci Lett 94:198–202

    Article  CAS  PubMed  Google Scholar 

  341. Yu WF, Guan ZZ, Bogdanovic N, Nordberg A (2005) High selective expression of α7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer’s disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques. Exp Neurol 192:215–225

    Article  CAS  PubMed  Google Scholar 

  342. Zhao J, O’Connor T, Vassar R (2011) The contribution of activated astrocytes to Abeta production: implications for Alzheimer’s disease pathogenesis. J Neuroinflammation 8:150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  343. Zhu CW, Sano M (2006) Economic considerations in the management of Alzheimer’s disease. Clin Interv Aging 1:143–154

    Article  PubMed  PubMed Central  Google Scholar 

  344. Ziemens D, Oschmann F, Gerkau NJ, Rose CR (2019) Heterogeneity of activity-induced sodium transients between astrocytes of the mouse hippocampus and neocortex: mechanisms and consequences. J Neurosci 39:2620–2634

    Article  PubMed  PubMed Central  Google Scholar 

  345. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201

    Article  CAS  PubMed  Google Scholar 

  346. 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

    Article  CAS  PubMed  Google Scholar 

  347. Zorec R, Parpura V, Vardjan N, Verkhratsky A (2017) Astrocytic face of Alzheimer’s disease. Behav Brain Res 322:250–257

    Article  CAS  PubMed  Google Scholar 

  348. Zorec R, Parpura V, Verkhratsky A (2018) Preventing neurodegeneration by adrenergic astroglial excitation. FEBS J 285:3645–3656

    Article  CAS  PubMed  Google Scholar 

  349. Zorec R, Verkhratsky A, Rodriguez JJ, Parpura V (2016) Astrocytic vesicles and gliotransmitters: Slowness of vesicular release and synaptobrevin2-laden vesicle nanoarchitecture. Neuroscience 323:67–75

    Article  CAS  PubMed  Google Scholar 

  350. Zott B, Busche MA, Sperling RA, Konnerth A (2018) What happens with the circuit in Alzheimer’s disease in mice and humans? Annu Rev Neurosci 41:277–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

VP’s work is supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health (R01GM123971). VP is an Honorary Professor at University of Rijeka, Croatia.

Author information

Authors and Affiliations

  1. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK

    Alexei Verkhratsky

  2. Faculty of Health and Medical Sciences, Center for Basic and Translational Neuroscience, University of Copenhagen, 2200, Copenhagen, Denmark

    Alexei Verkhratsky

  3. Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain

    Alexei Verkhratsky

  4. Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA

    Vladimir Parpura

  5. University of Rijeka, Rijeka, Croatia

    Vladimir Parpura

  6. BioCruces Health Research Institute, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

    Jose Julio Rodriguez-Arellano

  7. Department of Neuroscience, The University of the Basque Country UPV/EHU, Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain

    Jose Julio Rodriguez-Arellano

  8. Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia

    Robert Zorec

  9. Celica BIOMEDICAL, Ljubljana, Slovenia

    Robert Zorec

Authors
  1. Alexei Verkhratsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vladimir Parpura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jose Julio Rodriguez-Arellano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Zorec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexei Verkhratsky .

Editor information

Editors and Affiliations

  1. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Alexei Verkhratsky

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Margaret S. Ho

  3. Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia

    Robert Zorec

  4. Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA

    Vladimir Parpura

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Verkhratsky, A., Parpura, V., Rodriguez-Arellano, J.J., Zorec, R. (2019). Astroglia in Alzheimer’s Disease. In: Verkhratsky, A., Ho, M., Zorec, R., Parpura, V. (eds) Neuroglia in Neurodegenerative Diseases. Advances in Experimental Medicine and Biology, vol 1175. Springer, Singapore. https://doi.org/10.1007/978-981-13-9913-8_11

Download citation

Publish with us

Policies and ethics

Search

Navigation