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. 2010 Oct;7(4):399–412. doi: 10.1016/j.nurt.2010.05.017

Astrocytes in Alzheimer’s disease

Alexei Verkhratsky 1,2,✉, Markel Olabarria 1, Harun N Noristani 1, Chia-Yu Yeh 1, Jose Julio Rodriguez 3,4,5,✉
PMCID: PMC5084302  PMID: 20880504

Summary

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.

Astroglial cells are engaged in neurological diseases by determining the progression and outcome of neuropathological process. Astrocytes are specifically involved in various neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and various forms of dementia. Recent evidence suggest that early stages of neurodegenerative processes are associated with atrophy of astroglia, which causes disruptions in synaptic connectivity, disbalance in neurotransmitter homeostasis, and neuronal death through increased excitotoxicity. At the later stages, astrocytes become activated and contribute to the neuroinflammatory component of neurodegeneration.

Key Words: Astrocytes, neuroglia, neurodegeneration, Alzheimer’s disease, dementia, Parkinson’s disease

Contributor Information

Alexei Verkhratsky, Email: alex.verkhratsky@manchester.ac.uk.

Jose Julio Rodriguez, Email: j.rodriguez-arellano@ikerbasque.org.

References

  • 1.Case RM, Eisner D, Gurney A, Jones O, Muallem S, Verkhratsky A. Evolution of calcium homeostasis: from birth of the first cell to an omnipresent signalling system. Cell Calcium. 2007;42:345–350. doi: 10.1016/j.ceca.2007.05.001. [DOI] [PubMed] [Google Scholar]
  • 2.Durell SR, Guy HR. A putative prokaryote voltage-gated Ca2+ channel with only one 6TM motif per subunit. Biochem Biophys Res Commun. 2001;281:741–746. doi: 10.1006/bbrc.2001.4408. [DOI] [PubMed] [Google Scholar]
  • 3.Matsushita T, Hirata H, Kusaka I. Calcium channels in bacteria. Purification and characterization. Ann N Y Acad Sci. 1989;560:426–429. [Google Scholar]
  • 4.Shemarova IV, Nesterov VP. Evolution of mechanisms of calcium signaling: the role of calcium ions in signal transduction in prokaryotes. Zh Evol Biokhim Fiziol. 2005;41:12–17. doi: 10.1007/s10893-005-0029-z. [DOI] [PubMed] [Google Scholar]
  • 5.Tisa LS, Sekelsky JJ, Adler J. Effects of organic antagonists of Ca2+, Na+, and K+ on chemotaxis and motility of Escherichia coli. J Bacteriol. 2000;182:4856–4861. doi: 10.1128/jb.182.17.4856-4861.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Eckert R, Brehm P. Ionic mechanisms of excitation in Paramecium. Annu Rev Biophys Bioeng. 1979;8:353–383. doi: 10.1146/annurev.bb.08.060179.002033. [DOI] [PubMed] [Google Scholar]
  • 7.Franciolini F, Petris A. Evolution of ionic channels of biological membranes. Mol Biol Evol. 1989;6:503–513. doi: 10.1093/oxfordjournals.molbev.a040562. [DOI] [PubMed] [Google Scholar]
  • 8.Koishi R, Xu H, Ren D, et al. A superfamily of voltage-gated sodium channels in bacteria. J Biol Chem. 2004;279:9532–9538. doi: 10.1074/jbc.M313100200. [DOI] [PubMed] [Google Scholar]
  • 9.Shemarova IV, Nesterov VP. Evolution of Ca2+ signaling mechanisms. Role of calcium ions in signal transduction in lower eukaryotes. Zh Evol Biokhim Fiziol. 2005;41:303–313. [PubMed] [Google Scholar]
  • 10.Ladenburger EM, Sehring IM, Kom I, Plattner H. Novel types of Ca2+ release channels participate in the secretory cycle of Paramecium cells. Mol Cell Biol. 2009;29:3605–3622. doi: 10.1128/MCB.01592-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Matt H, Plattner H, Reichel K, Lefort-Tran M, Beisson J. Genetic dissection of the final exocytosis steps in Paramecium tetraurelia cells: trigger analyses. J Cell Sci. 1980;46:41–60. doi: 10.1242/jcs.46.1.41. [DOI] [PubMed] [Google Scholar]
  • 12.Plattner H, Reichel K, Matt H, Beisson J, Lefort-Tran M, Pouphile M. Genetic dissection of the final exocytosis steps in Paramecium tetraurelia cells: cytochemical determination of Ca2+-ATPase activity over performed exocytosis sites. J Cell Sci. 1980;46:17–40. doi: 10.1242/jcs.46.1.17. [DOI] [PubMed] [Google Scholar]
  • 13.Burnstock G, Verkhratsky A. Evolutionary origins of the purinergic signalling system. Acta Physiol (Oxf) 2009;195:415–447. doi: 10.1111/j.1748-1716.2009.01957.x. [DOI] [PubMed] [Google Scholar]
  • 14.Sakaguchi M, Mizusina A, Kobayakawa Y. Structure, development, and maintenance of the nerve net of the body column in Hydra. J Comp Neurol. 1996;373:41–54. doi: 10.1002/(SICI)1096-9861(19960909)373:1<41::AID-CNE4>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  • 15.Bacaj T, Tevlin M, Lu Y, Shaham S. Glia are essential for sensory organ function in C. elegans. Science. 2008;322:744–747. doi: 10.1126/science.1163074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Reichenbach A, Pannicke T. Neuroscience. A new glance at glia. Science. 2008;322:693–694. doi: 10.1126/science.1166197. [DOI] [PubMed] [Google Scholar]
  • 17.Verkhratsky A, Butt A. Glial neurobiology. A textbook. Chichester: John Wiley & Sons; 2007. [Google Scholar]
  • 18.Oberheim NA, Takano T, Han X, et al. Uniquely hominid features of adult human astrocytes. J Neurosci. 2009;29:3276–3287. doi: 10.1523/JNEUROSCI.4707-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the human brain. Trends Neurosci. 2006;29:547–553. doi: 10.1016/j.tins.2006.08.004. [DOI] [PubMed] [Google Scholar]
  • 20.Bushong EA, Martone ME, Ellisman MH. Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development. Int J Dev Neurosci. 2004;22:73–86. doi: 10.1016/j.ijdevneu.2003.12.008. [DOI] [PubMed] [Google Scholar]
  • 21.Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22:183–192. doi: 10.1523/JNEUROSCI.22-01-00183.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 2003;26:523–530. doi: 10.1016/j.tins.2003.08.008. [DOI] [PubMed] [Google Scholar]
  • 23.Iadecola C, Nedergaard M. Glial regulation of the cerebral microvasculature. Nat Neurosci. 2007;10:1369–1376. doi: 10.1038/nn2003. [DOI] [PubMed] [Google Scholar]
  • 24.Mulligan SJ, MacVicar BA. Calcium transients in astrocyte end-feet cause cerebrovascular constrictions. Nature. 2004;431:195–199. doi: 10.1038/nature02827. [DOI] [PubMed] [Google Scholar]
  • 25.Takano T, Tian GF, Peng W, et al. Astrocyte-mediated control of cerebral blood flow. Nat Neurosci. 2006;9:260–267. doi: 10.1038/nn1623. [DOI] [PubMed] [Google Scholar]
  • 26.Zonta M, Angulo MC, Gobbo S, et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci. 2003;6:43–50. doi: 10.1038/nn980. [DOI] [PubMed] [Google Scholar]
  • 27.Magistretti PJ. Neuron-glia metabolic coupling and plasticity. J Exp Biol. 2006;209:2304–2311. doi: 10.1242/jeb.02208. [DOI] [PubMed] [Google Scholar]
  • 28.Magistretti PJ. Role of glutamate in neuron-glia metabolic coupling. Am J Clin Nute. 2009;90:875S–880S. doi: 10.3945/ajcn.2009.27462CC. [DOI] [PubMed] [Google Scholar]
  • 29.Kofuji P, Newman EA. Potassium buffering in the central nervous system. Neuroscience. 2004;129:1045–1056. doi: 10.1016/j.neuroscience.2004.06.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Newman EA, Frambach DA, Odette LL. Control of extracellular potassium levels by retinal glial cell K+ siphoning. Science. 1984;225:1174–1175. doi: 10.1126/science.6474173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Simard M, Nedergaard M. The neurobiology of glia in the context of water and ion homeostasis. Neuroscience. 2004;129:877–896. doi: 10.1016/j.neuroscience.2004.09.053. [DOI] [PubMed] [Google Scholar]
  • 32.Swanson RA. Astrocyte neurotransmitter uptake. In: Kettenmann H, Ransom B, editors. Neuroglia. Oxford: Oxford University Press; 2005. pp. 346–354. [Google Scholar]
  • 33.Verkhratsky A, Kirchhoff F. Glutamate-mediated neuronal-glial transmission. J Anat. 2007;210:651–660. doi: 10.1111/j.1469-7580.2007.00734.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Danbolt NC. Glutamate uptake. Progr Neurobiol. 2001;65:1–105. doi: 10.1016/s0301-0082(00)00067-8. [DOI] [PubMed] [Google Scholar]
  • 35.Zerangue N, Kavanaugh MP. Flux coupling in a neuronal glutamate transporter. Nature. 1996;383:634–637. doi: 10.1038/383634a0. [DOI] [PubMed] [Google Scholar]
  • 36.Kirischuk S, Kettenmann H, Verkhratsky A. Membrane currents and cytoplasmic sodium transients generated by glutamate transport in Bergmann glial cells. Pflugers Arch. 2007;454:245–252. doi: 10.1007/s00424-007-0207-5. [DOI] [PubMed] [Google Scholar]
  • 37.Kirischuk S, Kettenmann H, Verkhratsky A. Na+/Ca2+ exchanger modulates kainate-triggered Ca2+ signaling in Bergmann glial cells in situ. Faseb J. 1997;11:566–572. doi: 10.1096/fasebj.11.7.9212080. [DOI] [PubMed] [Google Scholar]
  • 38.Minelli A, Castaldo P, Gobbi P, Salucci S, Magi S, Amoroso S. Cellular and subcellular localization of Na+-Ca2+ exchanger protein isoforms, NCX1, NCX2, and NCX3 in cerebral cortex and hippocampus of adult rat. Cell Calcium. 2007;41:221–234. doi: 10.1016/j.ceca.2006.06.004. [DOI] [PubMed] [Google Scholar]
  • 39.Martinez-Hernandez A, Bell KP, Norenberg MD. Glutamine synthetase: glial localization in brain. Science. 1977;195:1356–1358. doi: 10.1126/science.14400. [DOI] [PubMed] [Google Scholar]
  • 40.Bowman CL, Kimelberg HK. Excitatory amino acids directly depolarize rat brain astrocytes in primary culture. Nature. 1984;311:656–659. doi: 10.1038/311656a0. [DOI] [PubMed] [Google Scholar]
  • 41.Kettenmann H, Backus KH, Schachner M. Aspartate, glutamate and gamma-aminobutyric acid depolarize cultured astrocytes. Neurosci Lett. 1984;52:25–29. doi: 10.1016/0304-3940(84)90345-8. [DOI] [PubMed] [Google Scholar]
  • 42.Kettenmann H, Gilbert P, Schachner M. Depolarization of cultured oligodendrocytes by glutamate and GABA. Neurosci Lett. 1984;47:271–276. doi: 10.1016/0304-3940(84)90525-1. [DOI] [PubMed] [Google Scholar]
  • 43.Bevan S, Chiu SY, Gray PT, Ritchie JM. The presence of voltage-gated sodium, potassium and chloride channels in rat cultured astrocytes. Proc R Soc Lond B Biol Sci. 1985;225:299–313. doi: 10.1098/rspb.1985.0063. [DOI] [PubMed] [Google Scholar]
  • 44.Blankenfeld GV, Verkhratsky AN, Kettenmann H. Ca2+ channel expression in the oligodendrocyte lineage. Eur J Neurosci. 1992;4:1035–1048. doi: 10.1111/j.1460-9568.1992.tb00130.x. [DOI] [PubMed] [Google Scholar]
  • 45.Dave V, Gordon GW, McCarthy KD. Cerebral type 2 astroglia are heterogeneous with respect to their ability to respond to neuroligands linked to calcium mobilization. Glia. 1991;4:440–447. doi: 10.1002/glia.440040503. [DOI] [PubMed] [Google Scholar]
  • 46.Enkvist MO, Holopainen I, Akerman KE. Glutamate receptor-linked changes in membrane potential and intracellular Ca2+ in primary rat astrocytes. Glia. 1989;2:397–402. doi: 10.1002/glia.440020602. [DOI] [PubMed] [Google Scholar]
  • 47.Glaum SR, Holzwarth JA, Miller RJ. Glutamate receptors activate Ca2+ mobilization and Ca2+ influx into astrocytes. Proc Natl Acad Sci U S A. 1990;87:3454–3458. doi: 10.1073/pnas.87.9.3454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.McCarthy KD, Salm AK. Pharmacologically-distinct subsets of astroglia can be identified by their calcium response to neuroligands. Neuroscience. 1991;41:325–333. doi: 10.1016/0306-4522(91)90330-q. [DOI] [PubMed] [Google Scholar]
  • 49.Pearce B, Murphy S, Jeremy J, Morrow C, Dandona P. ATP-evoked Ca2+ mobilisation and prostanoid release from astrocytes: P2-purinergic receptors linked to phosphoinositide hydrolysis. J Neurochem. 1989;52:971–977. doi: 10.1111/j.1471-4159.1989.tb02549.x. [DOI] [PubMed] [Google Scholar]
  • 50.Sontheimer H, Ransom BR, Cornell Bell AH, Black JA, Waxman SG. Na+-current expression in rat hippocampal astrocytes in vitro: alterations during development. J Neurophysiol. 1991;65:3–19. doi: 10.1152/jn.1991.65.1.3. [DOI] [PubMed] [Google Scholar]
  • 51.Verkhratsky AN, Trotter J, Kettenmann H. Cultured glial precursor cells from mouse cortex express two types of calcium currents. Neurosci Lett. 1990;112:194–198. doi: 10.1016/0304-3940(90)90202-k. [DOI] [PubMed] [Google Scholar]
  • 52.Verkhratsky A, Shmigol A. Calcium-induced calcium release in neurones. Cell Calcium. 1996;19:1–14. doi: 10.1016/s0143-4160(96)90009-3. [DOI] [PubMed] [Google Scholar]
  • 53.Kirischuk S, Scherer J, Moller T, Verkhratsky A, Kettenmann H. Subcellular heterogeneity of voltage-gated Ca2+ channels in cells of the oligodendrocyte lineage. Glia. 1995;13:1–12. doi: 10.1002/glia.440130102. [DOI] [PubMed] [Google Scholar]
  • 54.Verkhratsky A, Steinhauser C. Ion channels in glial cells. Brain Res Brain Res Rev. 2000;32:380–412. doi: 10.1016/s0165-0173(99)00093-4. [DOI] [PubMed] [Google Scholar]
  • 55.Rodriguez JJ, Mackie K, Pickel VM. Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci. 2001;21:823–833. doi: 10.1523/JNEUROSCI.21-03-00823.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Kirischuk S, Moller T, Voitenko N, Kettenmann H, Verkhratsky A. ATP-induced cytoplasmic calcium mobilization in Bergmann glial cells. J Neurosci. 1995;15:7861–7871. doi: 10.1523/JNEUROSCI.15-12-07861.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Kirischuk S, Tuschick S, Verkhratsky A, Kettenmann H. Calcium signalling in mouse Bergmann glial cells mediated by a1-adreno-receptors and H1 histamine receptors. Eur J Neurosci. 1996;8:1198–1208. doi: 10.1111/j.1460-9568.1996.tb01288.x. [DOI] [PubMed] [Google Scholar]
  • 58.Kirischuk S, Matiash V, Kulik A, Voitenko N, Kostyuk P, Verkhratsky A. Activation of P2-purino-, a1-adreno and H1-histamine receptors triggers cytoplasmic calcium signalling in cerebellar Purkinje neurons. Neuroscience. 1996;73:643–647. doi: 10.1016/0306-4522(96)00205-9. [DOI] [PubMed] [Google Scholar]
  • 59.Verkhratsky A, Orkand RK, Kettenmann H. Glial calcium: homeostasis and signaling function. Physiol Rev. 1998;78:99–141. doi: 10.1152/physrev.1998.78.1.99. [DOI] [PubMed] [Google Scholar]
  • 60.Kirischuk S, Kirchhoff F, Matyash V, Kettenmann H, Verkhratsky A. Glutamate-triggered calcium signalling in mouse Bergmann glial cells in situ: role of inositol-1,4,5-trisphosphate-mediated intracellular calcium release. Neuroscience. 1999;92:1051–1059. doi: 10.1016/s0306-4522(99)00067-6. [DOI] [PubMed] [Google Scholar]
  • 61.Verkhratsky A, Krishtal OA, Burnstock G. Purinoceptors on neuroglia. Mol Neurobiol. 2009;39:190–208. doi: 10.1007/s12035-009-8063-2. [DOI] [PubMed] [Google Scholar]
  • 62.Verkhratsky A, Kirchhoff F. NMDA Receptors in Glia. Neuroscientist. 2007;13:28–37. doi: 10.1177/1073858406294270. [DOI] [PubMed] [Google Scholar]
  • 63.Karadottir R, Cavelier P, Bergeisen LH, Attwell D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature. 2005;438:1162–1166. doi: 10.1038/nature04302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A. NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci. 2006;26:2673–2683. doi: 10.1523/JNEUROSCI.4689-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Lipton SA. NMDA receptors, glial cells, and clinical medicine. Neuron. 2006;50:9–11. doi: 10.1016/j.neuron.2006.03.026. [DOI] [PubMed] [Google Scholar]
  • 66.Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999;22:208–215. doi: 10.1016/s0166-2236(98)01349-6. [DOI] [PubMed] [Google Scholar]
  • 67.Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med. 2007;13:54–63. doi: 10.1016/j.molmed.2006.12.005. [DOI] [PubMed] [Google Scholar]
  • 68.Giaume C, Venance L. Intercellular calcium signaling and gap junctional communication in astrocytes. Glia. 1998;24:50–64. [PubMed] [Google Scholar]
  • 69.Giaume C, Maravall M, Welker E, Bonvento G. The barrel cortex as a model to study dynamic neuroglial interaction. Neuroscientist. 2009;15:351–366. doi: 10.1177/1073858409336092. [DOI] [PubMed] [Google Scholar]
  • 70.Houades V, Koulakoff A, Ezan P, Seif I, Giaume C. Gap junction-mediated astrocytic networks in the mouse barrel cortex. J Neurosci. 2008;28:5207–5217. doi: 10.1523/JNEUROSCI.5100-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Berridge MJ. The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium. 2002;32:235–249. doi: 10.1016/s0143416002001823. [DOI] [PubMed] [Google Scholar]
  • 72.Berridge MJ, Irvine RF. Inositol phosphates and cell signalling. Nature. 1989;341:197–205. doi: 10.1038/341197a0. [DOI] [PubMed] [Google Scholar]
  • 73.Verkhratsky A, Petersen OH. The endoplasmic reticulum as an integrating signalling organelle: from neuronal signalling to neuronal death. Eur J Pharmacol. 2002;447:141–154. doi: 10.1016/s0014-2999(02)01838-1. [DOI] [PubMed] [Google Scholar]
  • 74.Verkhratsky A. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev. 2005;85:201–279. doi: 10.1152/physrev.00004.2004. [DOI] [PubMed] [Google Scholar]
  • 75.Kostyuk P, Verkhratsky A. Calcium stores in neurons and glia. Neuroscience. 1994;63:381–404. doi: 10.1016/0306-4522(94)90537-1. [DOI] [PubMed] [Google Scholar]
  • 76.Petersen OH, Michalak M, Verkhratsky A. Calcium signalling: Past, present and future. Cell Calcium. 2005;38:161–169. doi: 10.1016/j.ceca.2005.06.023. [DOI] [PubMed] [Google Scholar]
  • 77.Verkhratsky A. Calcium ions and integration in neural circuits. Acta Physiol (Oxf) 2006;187:357–369. doi: 10.1111/j.1748-1716.2006.01566.x. [DOI] [PubMed] [Google Scholar]
  • 78.Burdakov D, Petersen OH, Verkhratsky A. Intraluminal calcium as a primary regulator of endoplasmic reticulum function. Cell Calcium. 2005;38:303–310. doi: 10.1016/j.ceca.2005.06.010. [DOI] [PubMed] [Google Scholar]
  • 79.Verkhratsky A. The endoplasmic reticulum and neuronal calcium signalling. Cell Calcium. 2002;32:393–404. doi: 10.1016/s0143416002001896. [DOI] [PubMed] [Google Scholar]
  • 80.Wuytack F, Raeymaekers L, Missiaen L. Molecular physiology of the SERCA and SPCA pumps. Cell Calcium. 2002;32:279–305. doi: 10.1016/s0143416002001847. [DOI] [PubMed] [Google Scholar]
  • 81.Solovyova N, Verkhratsky A. Monitoring of free calcium in the neuronal endoplasmic reticulum: an overview of modern approaches. J Neurosci Methods. 2002;122:1–12. doi: 10.1016/s0165-0270(02)00300-x. [DOI] [PubMed] [Google Scholar]
  • 82.Solovyova N, Veselovsky N, Toescu EC, Verkhratsky A. Ca2+ dynamics in the lumen of the endoplasmic reticulum in sensory neurons: direct visualization of Ca2+-induced Ca2+ release triggered by physiological Ca2+ entry. Embo J. 2002;21:622–630. doi: 10.1093/emboj/21.4.622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Petersen OH, Tepikin A, Park MK. The endoplasmic reticulum: one continuous or several separate Ca2+ stores? Trends Neurosci. 2001;24:27127–6. doi: 10.1016/s0166-2236(00)01787-2. [DOI] [PubMed] [Google Scholar]
  • 84.Solovyova N, Verkhratsky A. Neuronal endoplasmic reticulum acts as a single functional Ca2+ store shared by ryanodine and inositol-1,4,5-trisphosphate receptors as revealed by intra-ER [Ca2+] recordings in single rat sensory neurones. Pflugers Arch. 2003;446:447–454. doi: 10.1007/s00424-003-1094-z. [DOI] [PubMed] [Google Scholar]
  • 85.Petersen OH, Verkhratsky A. Endoplasmic reticulum calcium tunnels integrate signalling in polarised cells. Cell Calcium. 2007;42:373–378. doi: 10.1016/j.ceca.2007.05.012. [DOI] [PubMed] [Google Scholar]
  • 86.Bezprozvanny I. The inositol 1,4,5-trisphosphate receptors. Cell Calcium. 2005;38:261–272. doi: 10.1016/j.ceca.2005.06.030. [DOI] [PubMed] [Google Scholar]
  • 87.Hamilton SL. Ryanodine receptors. Cell Calcium. 2005;38:253–260. doi: 10.1016/j.ceca.2005.06.037. [DOI] [PubMed] [Google Scholar]
  • 88.Deitmer JW, Verkhratsky AJ, Lohr C. Calcium signalling in glial cells. Cell Calcium. 1998;24:405–416. doi: 10.1016/s0143-4160(98)90063-x. [DOI] [PubMed] [Google Scholar]
  • 89.Grosche J, Matyash V, Moller T, Verkhratsky A, Reichenbach A, Kettenmann H. Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci. 1999;2:139–143. doi: 10.1038/5692. [DOI] [PubMed] [Google Scholar]
  • 90.Cornell Bell AH, Finkbeiner SM, Cooper MS, Smith SJ. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science. 1990;247:470–473. doi: 10.1126/science.1967852. [DOI] [PubMed] [Google Scholar]
  • 91.Dani JW, Chemjavsky A, Smith SJ. Neuronal activity triggers calcium waves in hippocampal astrocyte networks. Neuron. 1992;8:429–440. doi: 10.1016/0896-6273(92)90271-e. [DOI] [PubMed] [Google Scholar]
  • 92.Scemes E, Giaume C. Astrocyte calcium waves: what they are and what they do. Glia. 2006;54:716–725. doi: 10.1002/glia.20374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Anderson CM, Bergher JP, Swanson RA. ATP-induced ATP release from astrocytes. J Neurochem. 2004;88:246–256. doi: 10.1111/j.1471-4159.2004.02204.x. [DOI] [PubMed] [Google Scholar]
  • 94.Arcuino G, Lin JH, Takano T, Liu C, Jiang L, Gao Q, et al. Intercellular calcium signaling mediated by point-source burst release of ATP. Proc Natl Acad Sci U S A. 2002;99:9840–9845. doi: 10.1073/pnas.152588599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Bennett MR, Famell L, Gibson WG. A quantitative model of purinergic junctional transmission of calcium waves in astrocyte networks. Biophys J. 2005;89:2235–2250. doi: 10.1529/biophysj.105.062968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Suadicani SO, Brosnan CF, Scemes E. P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J Neurosci. 2006;26:1378–1385. doi: 10.1523/JNEUROSCI.3902-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Angulo MC, Le Meur K, Kozlov AS, Charpak S, Audinat E. GABA, a forgotten gliotransmitter. Prog Neurobiol. 2008;86:297–303. doi: 10.1016/j.pneurobio.2008.08.002. [DOI] [PubMed] [Google Scholar]
  • 98.Bezzi P, Carmignoto G, Pasti L, et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature. 1998;391:281–285. doi: 10.1038/34651. [DOI] [PubMed] [Google Scholar]
  • 99.Bezzi P, Gundersen V, Galbete JL, et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci. 2004;7:613–620. doi: 10.1038/nn1246. [DOI] [PubMed] [Google Scholar]
  • 100.Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729–743. doi: 10.1016/j.neuron.2004.08.011. [DOI] [PubMed] [Google Scholar]
  • 101.Jourdain P, Bergeisen LH, Bhaukaurally K, et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci. 2007;10:331–339. doi: 10.1038/nn1849. [DOI] [PubMed] [Google Scholar]
  • 102.Oliet SH, Mothet JP. Regulation of N-methyl-D-aspartate receptors by astrocytic D-serine. Neuroscience. 2009;158:275–283. doi: 10.1016/j.neuroscience.2008.01.071. [DOI] [PubMed] [Google Scholar]
  • 103.Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci. 2005;6:626–640. doi: 10.1038/nrn1722. [DOI] [PubMed] [Google Scholar]
  • 104.Montana V, Malaikey EB, Verderio C, Matteoli M, Parpura V. Vesicular transmitter release from astrocytes. Glia. 2006;54:700–715. doi: 10.1002/glia.20367. [DOI] [PubMed] [Google Scholar]
  • 105.Parpura V, Mohideen U. Molecular form follows function: (un-)snaring the SNAREs. Trends Neurosci. 2008;31:435–443. doi: 10.1016/j.tins.2008.06.003. [DOI] [PubMed] [Google Scholar]
  • 106.Reyes RC, Parpura V. The trinity of Ca2+ sources for the exocytotic glutamate release from astrocytes. Neurochem Int. 2009;55:2–8. doi: 10.1016/j.neuint.2008.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Cotrina ML, Lin JH, Alves-Rodrigues A, et al. Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci U S A. 1998;95:15735–15740. doi: 10.1073/pnas.95.26.15735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Duan S, Anderson CM, Keung EC, Chen Y, Swanson RA. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci. 2003;23:1320–1328. doi: 10.1523/JNEUROSCI.23-04-01320.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Kang J, Kang N, Lovatt D, et al. Connexin 43 hemichannels are permeable to ATP. J Neurosci. 2008;28:4702–4711. doi: 10.1523/JNEUROSCI.5048-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Pankratov Y, Lalo U, Verkhratsky A, North RA. Vesicular release of ATP at central synapses. Pflugers Arch. 2006;452:589–597. doi: 10.1007/s00424-006-0061-x. [DOI] [PubMed] [Google Scholar]
  • 111.Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421–431. doi: 10.1016/j.tins.2009.05.001. [DOI] [PubMed] [Google Scholar]
  • 112.Alzheimer A. Beiträge zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgängen im Nervengewebe. In: Nissl F, Alzheimer A, editors. Histologische und Histopathologische Arbeiten über die Grosshirnrinde mit besonderer Berücksichtigung der pathologischen Anatomie der Geisteskrankheiten. Jena: Verlag von Gustav Fischer; 1910. pp. 401–562. [Google Scholar]
  • 113.Frommann C. Untersuchungen über die Gewebsveränderungen bei der Multiplen Sklerose des Gehirns und Rückenmarks. Jena: Verlag von Gustav Fischer; 1878. [Google Scholar]
  • 114.Nissl F. Ueber einige Beziehungen zwischen Nervenzellerkrankungen und gliösen Erscheinungen bei verschiedenen Psychosen. Arch. Psychiat. 1899;32:1–21. [Google Scholar]
  • 115.Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A. Glia: the fulcrum of brain diseases. Cell Death Differ. 2007;14:1324–1335. doi: 10.1038/sj.cdd.4402144. [DOI] [PubMed] [Google Scholar]
  • 116.Nedergaard M, Rodriguez JJ, Verkhratsky A. Glial calcium and diseases of the nervous system. Cell Calcium. 2010;47:140–149. doi: 10.1016/j.ceca.2009.11.010. [DOI] [PubMed] [Google Scholar]
  • 117.Nedergaard M, Dirnagl U. Role of glial cells in cerebral ischemia. Glia. 2005;50:281–286. doi: 10.1002/glia.20205. [DOI] [PubMed] [Google Scholar]
  • 118.Li L, Lundkvist A, Andersson D, et al. Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab. 2008;28:468–481. doi: 10.1038/sj.jcbfm.9600546. [DOI] [PubMed] [Google Scholar]
  • 119.Pekny M, Nilsson M. Astrocyte activation and reactive gliosis. Glia. 2005;50:427–434. doi: 10.1002/glia.20207. [DOI] [PubMed] [Google Scholar]
  • 120.Rossi D, Volterra A. Astrocytic dysfunction: Insights on the role in neurodegeneration. Brain Res Bull. 2009;80:224–232. doi: 10.1016/j.brainresbull.2009.07.012. [DOI] [PubMed] [Google Scholar]
  • 121.Jabs R, Seifert G, Steinhauser C. Astrocytic function and its alteration in the epileptic brain. Epilepsia. 2008;49(suppl 2):3–12. doi: 10.1111/j.1528-1167.2008.01488.x. [DOI] [PubMed] [Google Scholar]
  • 122.Seifert G, Schilling K, Steinhauser C. Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci. 2006;7:194–206. doi: 10.1038/nrn1870. [DOI] [PubMed] [Google Scholar]
  • 123.Tsai G, Coyle JT. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol. 2002;42:165–179. doi: 10.1146/annurev.pharmtox.42.082701.160735. [DOI] [PubMed] [Google Scholar]
  • 124.Heneka MT, Rodriguez JJ, Verkhratsky A. Neuroglia in neurodegeneration. Brain Res Rev. 2010;63:189–211. doi: 10.1016/j.brainresrev.2009.11.004. [DOI] [PubMed] [Google Scholar]
  • 125.Kano M, Hashimoto K. Synapse elimination in the central nervous system. Curr Opin Neurobiol. 2009;19:154–161. doi: 10.1016/j.conb.2009.05.002. [DOI] [PubMed] [Google Scholar]
  • 126.Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007;68:1501–1508. doi: 10.1212/01.wnl.0000260698.46517.8f. [DOI] [PubMed] [Google Scholar]
  • 127.Terry RD. Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol. 2000;59:1118–1119. doi: 10.1093/jnen/59.12.1118. [DOI] [PubMed] [Google Scholar]
  • 128.Charcot JM. Lectures on diseases of the nervous system. London: New Sydenham Society; 1881. Amyotrophic lateral sclerosis: symptomatology; pp. 192–204. [Google Scholar]
  • 129.Charcot JM, Joffroy A. Deux cas d’atrophie musculaire progressive avec lesions de la substance grise et de faisceaux anterolateraux de la moelle epiniere. Arch Physiol Norm Pathol. 1869;1:354–367. [Google Scholar]
  • 130.Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol. 2008;85:94–134. doi: 10.1016/j.pneurobio.2008.01.001. [DOI] [PubMed] [Google Scholar]
  • 131.Rossi D, Brambilla L, Valori CF, et al. Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell Death Differ. 2008;15:1691–1700. doi: 10.1038/cdd.2008.99. [DOI] [PubMed] [Google Scholar]
  • 132.Yamanaka K, Chun SJ, Boillee S, et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008;11:251–253. doi: 10.1038/nn2047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133.Johansson A, Engler H, Blomquist G, et al. Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET. J Neurol Sci. 2007;255:17–22. doi: 10.1016/j.jns.2007.01.057. [DOI] [PubMed] [Google Scholar]
  • 134.McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002;26:459–470. doi: 10.1002/mus.10191. [DOI] [PubMed] [Google Scholar]
  • 135.Parkinson J. An Essay on the Shaking Palsy. London: Sherwood, Neely, and Jones; 1817. [Google Scholar]
  • 136.McGeer PL, McGeer EG. Glial reactions in Parkinson’s disease. Mov Disord. 2008;23:474–483. doi: 10.1002/mds.21751. [DOI] [PubMed] [Google Scholar]
  • 137.Mena MA, Garcia de Yebenes J. Glial cells as players in parkinsonism: the “good,” the “bad,” and the “mysterious” glia. Neuroscientist. 2008;14:544–560. doi: 10.1177/1073858408322839. [DOI] [PubMed] [Google Scholar]
  • 138.Broe M, Kril J, Halliday GM. Astrocytic degeneration relates to the severity of disease in frontotemporal dementia. Brain. 2004;127:2214–2220. doi: 10.1093/brain/awh250. [DOI] [PubMed] [Google Scholar]
  • 139.Kersaitis C, Halliday GM, Kril JJ. Regional and cellular pathology in frontotemporal dementia: relationship to stage of disease in cases with and without Pick bodies. Acta Neuropathol. 2004;108:515–523. doi: 10.1007/s00401-004-0917-0. [DOI] [PubMed] [Google Scholar]
  • 140.Potts R, Leech RW. Thalamic dementia: an example of primary astroglial dystrophy of Seitelberger. Clin Neuropathol. 2005;24:271–275. [PubMed] [Google Scholar]
  • 141.Thompson KA, McArthur JC, Wesselingh SL. Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia. Ann Neurol. 2001;49:745–752. doi: 10.1002/ana.1011. [DOI] [PubMed] [Google Scholar]
  • 142.Vanzani MC, Iacono RF, Caccuri RL, Troncoso AR, Berria MI. Regional differences in astrocyte activation in HIV-associated dementia. Medicina (B Aires) 2006;66:108–112. [PubMed] [Google Scholar]
  • 143.Dabir DV, Trojanowski JQ, Richter-Landsberg C, Lee VM, Forman MS. Expression of the small heat-shock protein aB-crystallin in tauopathies with glial pathology. Am J Pathol. 2004;164:155–166. doi: 10.1016/s0002-9440(10)63106-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 144.Forman MS, Lal D, Zhang B, et al. Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J Neurosci. 2005;25:3539–3550. doi: 10.1523/JNEUROSCI.0081-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 145.Hazell AS. Astrocytes are a major target in thiamine deficiency and Wemicke’s encephalopathy. Neurochem Int. 2009;55:129–135. doi: 10.1016/j.neuint.2009.02.020. [DOI] [PubMed] [Google Scholar]
  • 146.Hazell AS, Sheedy D, Oanea R, et al. Loss of astrocytic glutamate transporters in Wemicke encephalopathy. Glia. 2009;58:148–156. doi: 10.1002/glia.20908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 147.Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY. Astrocytes accumulate A b 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971:197–209. doi: 10.1016/s0006-8993(03)02361-8. [DOI] [PubMed] [Google Scholar]
  • 148.Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging. 2004;25:663–674. doi: 10.1016/j.neurobiolaging.2004.01.007. [DOI] [PubMed] [Google Scholar]
  • 149.Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A. Astroglia in dementia and Alzheimer’s disease. Cell Death Differ. 2009;16:378–385. doi: 10.1038/cdd.2008.172. [DOI] [PubMed] [Google Scholar]
  • 150.Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia. 2010;58:831–838. doi: 10.1002/glia.20967. [DOI] [PubMed] [Google Scholar]
  • 151.Beach TG, McGeer EG. Lamina-specific arrangement of astrocytic gliosis and senile plaques in Alzheimer’s disease visual cortex. Brain Res. 1988;463:357–361. doi: 10.1016/0006-8993(88)90410-6. [DOI] [PubMed] [Google Scholar]
  • 152.Griffin WS, Stanley LC, Ling C, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989;86:7611–7615. doi: 10.1073/pnas.86.19.7611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 153.Kashon ML, Ross GW, O’Callaghan JP, et al. Associations of cortical astrogliosis with cognitive performance and dementia status. J Alzheimers Dis. 2004;6:595–604. doi: 10.3233/jad-2004-6604. [DOI] [PubMed] [Google Scholar]
  • 154.Mrak RE, Griffin WS. Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging. 2005;26:349–354. doi: 10.1016/j.neurobiolaging.2004.05.010. [DOI] [PubMed] [Google Scholar]
  • 155.Sheng JG, Mrak RE, Rovnaghi CR, Kozlowska E, Van Eldik LJ, Griffin WS. Human brain S100 beta and S100 beta mRNA expression increases with age: pathogenic implications for Alzheimer’s disease. Neurobiol Aging. 1996;17:359–363. doi: 10.1016/0197-4580(96)00037-1. [DOI] [PubMed] [Google Scholar]
  • 156.Meda L, Baron P, Scarlato G. Glial activation in Alzheimer’s disease: the role of Abeta and its associated proteins. Neurobiol Aging. 2001;22:885–893. doi: 10.1016/s0197-4580(01)00307-4. [DOI] [PubMed] [Google Scholar]
  • 157.Simpson JE, Ince PG, Lace G, et al. Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging. 2010;31:578–590. doi: 10.1016/j.neurobiolaging.2008.05.015. [DOI] [PubMed] [Google Scholar]
  • 158.Wharton SB, O’Callaghan JP, Savva GM, et al. Population variation in glial fibrillary acidic protein levels in brain aging: relationship to Alzheimer-type pathology and dementia. Dement Geriatr Cogn Disord. 2009;27:465–473. doi: 10.1159/000217729. [DOI] [PubMed] [Google Scholar]
  • 159.Mansour H, Chamberlain CG, Weible MW, Hughes S, Chu Y, Chan-Ling T. Aging-related changes in astrocytes in the rat retina: imbalance between cell proliferation and cell death reduces astrocyte availability. Aging Cell. 2008;7:526–540. doi: 10.1111/j.1474-9726.2008.00402.x. [DOI] [PubMed] [Google Scholar]
  • 160.Ramirez JM, Ramirez AI, Salazar JJ, de Hoz R, Trivino A. Changes of astrocytes in retinal ageing and age-related macular degeneration. Exp Eye Res. 2001;73:601–615. doi: 10.1006/exer.2001.1061. [DOI] [PubMed] [Google Scholar]
  • 161.Mouton PR, Long JM, Lei DL, et al. Age and gender effects on microglia and astrocyte numbers in brains of mice. Brain Res. 2002;956:30–35. doi: 10.1016/s0006-8993(02)03475-3. [DOI] [PubMed] [Google Scholar]
  • 162.Amenta F, Bronzetti E, Sabbatini M, Vega JA. Astrocyte changes in aging cerebral cortex and hippocampus: a quantitative immunohistochemical study. Microsc Res Tech. 1998;43:29–33. doi: 10.1002/(SICI)1097-0029(19981001)43:1<29::AID-JEMT5>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  • 163.Peinado MA, Quesada A, Pedrosa JA, et al. Quantitative and ultrastructural changes in glia and pericytes in the parietal cortex of the aging rat. Microsc Res Tech. 1998;43:34–42. doi: 10.1002/(SICI)1097-0029(19981001)43:1<34::AID-JEMT6>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  • 164.Pilegaard K, Ladefoged O. Total number of astrocytes in the molecular layer of the dentate gyrus of rats at different ages. Anal Quant Cytol Histol. 1996;18:279–285. [PubMed] [Google Scholar]
  • 165.Peters A, Verderosa A, Sethares C. The neuroglial population in the primary visual cortex of the aging rhesus monkey. Glia. 2008;56:1151–1161. doi: 10.1002/glia.20686. [DOI] [PubMed] [Google Scholar]
  • 166.Pakkenberg B, Pelvig D, Marner L, et al. Aging and the human neocortex. Exp Gerontol. 2003;38:95–99. doi: 10.1016/s0531-5565(02)00151-1. [DOI] [PubMed] [Google Scholar]
  • 167.Hinman JD, Abraham CR. What’s behind the decline? The role of white matter in brain aging. Neurochem Res. 2007;32:2023–2031. doi: 10.1007/s11064-007-9341-x. [DOI] [PubMed] [Google Scholar]
  • 168.Cotrina ML, Nedergaard M. Astrocytes in the aging brain. J Neurosci Res. 2002;67:1–10. doi: 10.1002/jnr.10121. [DOI] [PubMed] [Google Scholar]
  • 169.DeWitt DA, Perry G, Cohen M, Doller C, Silver J. Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer’s disease. Exp Neurol. 1998;149:329–340. doi: 10.1006/exnr.1997.6738. [DOI] [PubMed] [Google Scholar]
  • 170.Abramov AY, Canevari L, Duchen MR. Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J Neurosci. 2003;23:5088–5095. doi: 10.1523/JNEUROSCI.23-12-05088.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 171.Abramov AY, Canevari L, Duchen MR. b-Amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci. 2004;24:565–575. doi: 10.1523/JNEUROSCI.4042-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 172.Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science. 2009;323:1211–1215. doi: 10.1126/science.1169096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 173.Peters O, Schipke CG, Philipps A, et al. Astrocyte function is modified by Alzheimer’s disease-like pathology in aged mice. J Alzheimers Dis. 2009;18:177–189. doi: 10.3233/JAD-2009-1140. [DOI] [PubMed] [Google Scholar]
  • 174.Matos M, Augusto E, Oliveira CR, Agostinho P. Amyloid-b peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades. Neuroscience. 2008;156:898–810. doi: 10.1016/j.neuroscience.2008.08.022. [DOI] [PubMed] [Google Scholar]
  • 175.Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Ab and synaptic dysfunction. Neuron. 2003;39:409–421. doi: 10.1016/s0896-6273(03)00434-3. [DOI] [PubMed] [Google Scholar]
  • 176.Kimelberg HK. The problem of astrocyte identity. Neurochem Int. 2004;45:191–202. doi: 10.1016/j.neuint.2003.08.015. [DOI] [PubMed] [Google Scholar]
  • 177.Senitz D, Reichenbach A, Smith TG. Surface complexity of human neocortical astrocytic cells: changes with development, aging, and dementia. J Hirnforsch. 1995;36:531–537. [PubMed] [Google Scholar]
  • 178.Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR. Alzheimer’s disease beta-secretase BACE1 is not a neuron-specific enzyme. J Neurochem. 2005;92:226–234. doi: 10.1111/j.1471-4159.2004.02857.x. [DOI] [PubMed] [Google Scholar]
  • 179.Guenette SY. Astrocytes: a cellular player in Abeta clearance and degradation. Trends Mol Med. 2003;9:279–280. doi: 10.1016/s1471-4914(03)00112-6. [DOI] [PubMed] [Google Scholar]
  • 180.Nicoll JA, Weller RO. A new role for astrocytes: beta-amyloid homeostasis and degradation. Trends Mol Med. 2003;9:281–282. doi: 10.1016/s1471-4914(03)00109-6. [DOI] [PubMed] [Google Scholar]
  • 181.Apelt J, Ach K, Schliebs R. Aging-related down-regulation of neprilysin, a putative beta-amyloid-degrading enzyme, in transgenic Tg2576 Alzheimer-like mouse brain is accompanied by an astroglial upregulation in the vicinity of beta-amyloid plaques. Neurosci Lett. 2003;339:183–186. doi: 10.1016/s0304-3940(03)00030-2. [DOI] [PubMed] [Google Scholar]
  • 182.Wyss-Coray T, Loike JD, Brionne TC, et al. Adult mouse astrocytes degrade amyloid-b in vitro and in situ. Nat Med. 2003;9:453–457. doi: 10.1038/nm838. [DOI] [PubMed] [Google Scholar]
  • 183.Rossner S, Apelt J, Schliebs R, Perez-Polo JR, Bigl V. Neuronal and glial beta-secretase (BACE) protein expression in transgenic Tg2576 mice with amyloid plaque pathology. J Neurosci Res. 2001;64:437–446. doi: 10.1002/jnr.1095. [DOI] [PubMed] [Google Scholar]
  • 184.Hartlage-Rubsamen M, Zeitschel U, Apelt J, et al. Astrocytic expression of the Alzheimer’s disease b-secretase (BACE1) is stimulus-dependent. Glia. 2003;41:169–179. doi: 10.1002/glia.10178. [DOI] [PubMed] [Google Scholar]
  • 185.Heneka MT, Sastre M, Dumitrescu-Ozimek L, et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflam. 2005;2:22–22. doi: 10.1186/1742-2094-2-22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 186.Martins RN, Taddei K, Kendall C, Evin G, Bates KA, Harvey AR. Altered expression of apolipoprotein E, amyloid precursor protein and presenilin-1 is associated with chronic reactive gliosis in rat cortical tissue. Neuroscience. 2001;106:557–569. doi: 10.1016/s0306-4522(01)00289-5. [DOI] [PubMed] [Google Scholar]
  • 187.Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol. 2009;118:103–113. doi: 10.1007/s00401-009-0522-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 188.Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci. 2004;5:347–360. doi: 10.1038/nrn1387. [DOI] [PubMed] [Google Scholar]
  • 189.Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201. doi: 10.1016/j.neuron.2008.01.003. [DOI] [PubMed] [Google Scholar]
  • 190.Farkas E, Luiten PG. Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol. 2001;64:575–611. doi: 10.1016/s0301-0082(00)00068-x. [DOI] [PubMed] [Google Scholar]
  • 191.Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53. doi: 10.1038/nrn1824. [DOI] [PubMed] [Google Scholar]
  • 192.Mosconi L, Pupi A, De Leon MJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci. 2008;1147:180–195. doi: 10.1196/annals.1427.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 193.Parpura-Gill A, Beitz D, Uemura E. The inhibitory effects of beta-amyloid on glutamate and glucose uptakes by cultured astrocytes. Brain Res. 1997;754:65–71. doi: 10.1016/s0006-8993(97)00043-7. [DOI] [PubMed] [Google Scholar]
  • 194.Schubert D, Soucek T, Blouw B. The induction of HIF-1 reduces astrocyte activation by amyloid beta peptide. Eur J Neurosci. 2009;29:1323–1334. doi: 10.1111/j.1460-9568.2009.06712.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 195.Soucek T, Cumming R, Dargusch R, Maher P, Schubert D. The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Neuron. 2003;39:43–56. doi: 10.1016/s0896-6273(03)00367-2. [DOI] [PubMed] [Google Scholar]
  • 196.Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, et al. Amyloid-b aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci. 2010;30:3326–3338. doi: 10.1523/JNEUROSCI.5098-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 197.Blass JP, Sheu RK, Gibson GE. Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise. Ann N Y Acad Sci. 2000;903:204–221. doi: 10.1111/j.1749-6632.2000.tb06370.x. [DOI] [PubMed] [Google Scholar]
  • 198.Liang WS, Reiman EM, Valla J, et al. Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A. 2008;105:4441–4446. doi: 10.1073/pnas.0709259105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 199.Bigl M, Bruckner MK, Arendt T, Bigl V, Eschrich K. Activities of key glycolytic enzymes in the brains of patients with Alzheimer’s disease. J Neural Transm. 1999;106:499–511. doi: 10.1007/s007020050174. [DOI] [PubMed] [Google Scholar]
  • 200.Coleman P, Federoff H, Kurlan R. A focus on the synapse for neuroprotection in Alzheimer disease and other dementias. Neurology. 2004;63:1155–1162. doi: 10.1212/01.wnl.0000140626.48118.0a. [DOI] [PubMed] [Google Scholar]
  • 201.Elias MF, Beiser A, Wolf PA, Au R, White RF, D’Agostino RB. The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort. Arch Neurol. 2000;57:808–813. doi: 10.1001/archneur.57.6.808. [DOI] [PubMed] [Google Scholar]
  • 202.DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–464. doi: 10.1002/ana.410270502. [DOI] [PubMed] [Google Scholar]
  • 203.Samuel W, Masliah E, Hill LR, Butters N, Terry R. Hippocampal connectivity and Alzheimer’s dementia: effects of synapse loss and tangle frequency in a two-component model. Neurology. 1994;44:2081–2088. doi: 10.1212/wnl.44.11.2081. [DOI] [PubMed] [Google Scholar]
  • 204.Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–580. doi: 10.1002/ana.410300410. [DOI] [PubMed] [Google Scholar]
  • 205.Alle H, Roth A, Geiger JR. Energy-efficient action potentials in hippocampal mossy fibers. Science. 2009;325:1405–1408. doi: 10.1126/science.1174331. [DOI] [PubMed] [Google Scholar]
  • 206.Magistretti PJ. Neuroscience. Low-cost travel in neurons. Science. 2009;325:1349–1351. doi: 10.1126/science.1180102. [DOI] [PubMed] [Google Scholar]
  • 207.Bilan Y, Masters CL, Barnham KJ, Bush AI, Adlard PA. Pharmacotherapeutic targets in Alzheimer’s disease. J Cell Mol Med. 2009;13:61–86. doi: 10.1111/j.1582-4934.2008.00595.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 208.McCall MA, Gregg RG, Behringer RR, et al. Targeted deletion in astrocyte intermediate filament (Gfap) alters neuronal physiology. Proc Natl Acad Sci U S A. 1996;93:6361–6366. doi: 10.1073/pnas.93.13.6361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 209.Shibuki K, Gomi H, Chen L, et al. Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in GFAP mutant mice. Neuron. 1996;16:587–599. doi: 10.1016/s0896-6273(00)80078-1. [DOI] [PubMed] [Google Scholar]
  • 210.Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255–262. doi: 10.1038/35041700. [DOI] [PubMed] [Google Scholar]
  • 211.Doble A. The pharmacology and mechanism of action of riluzole. Neurology. 1996;47:S233–S241. doi: 10.1212/wnl.47.6_suppl_4.233s. [DOI] [PubMed] [Google Scholar]
  • 212.Frizzo ME, Dall’Onder LP, Dalcin KB, Souza DO. Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol. 2004;24:123–128. doi: 10.1023/B:CEMN.0000012717.37839.07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 213.Ji HF, Shen L, Zhang HY. Beta-lactam antibiotics are multipotent agents to combat neurological diseases. Biochem Biophys Res Commun. 2005;333:661–663. doi: 10.1016/j.bbrc.2005.05.014. [DOI] [PubMed] [Google Scholar]
  • 214.Blackburn D, Sargsyan S, Monk PN, Shaw PJ. Astrocyte function and role in motor neuron disease: a future therapeutic target? Glia. 2009;57:1251–1264. doi: 10.1002/glia.20848. [DOI] [PubMed] [Google Scholar]

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