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Cell and Tissue Research

, Volume 357, Issue 2, pp 427–438 | Cite as

Network-wide dysregulation of calcium homeostasis in Alzheimer’s disease

  • Bianca Brawek
  • Olga GaraschukEmail author
Review

Abstract

Dysregulation of intracellular Ca2+ homeostasis has been proposed as a common proximal cause of neural dysfunction during aging and Alzheimer’s disease (AD). In this context, aberrant Ca2+ signaling has been viewed as a neuronal phenomenon mostly related to the dysfunction of intracellular Ca2+ stores. However, recent data suggest that, in AD, Ca2+ dyshomeostasis is not restricted to neurons but represents a global phenomenon affecting virtually all cells in the brain. AD-related aberrant Ca2+ signaling in astrocytes and microglia, which is activated during the disease, probably contributes profoundly to an inflammatory response that, in turn, impacts neuronal Ca2+ homeostasis and brain function. Based on recent data obtained in vivo and in vitro, we propose that bidirectional interactions between the inflammatory responses of glial cells and aberrant Ca2+ signaling represent a vicious cycle accelerating disease progression.

Keywords

Neurodegeneration Calcium homeostasis Hyperexcitability Glia Inflammation 

Abbreviations

AD

Alzheimer’s disease

AMPA

α-Amino-3-hydroxy-5-methylisoxazole-4-proprionic acid

APP

Amyloid precursor protein

Amyloid β

[Ca2+]e

Extracellular free Ca2+ concentration

[Ca2+]i

Intracellular free Ca2+ concentration

CaN

Calcineurin

DICT

Damage-induced Ca2+ transient

GABA

Gamma-aminobutyric acid

IFN-γ

Interferon-γ

IL

Interleukin

IP3

Inositol trisphosphate

IP3R

Inositol trisphosphate receptor

LPS

Lipopolysaccharide

NFAT

Nuclear factor of activated T-cells

NLRP3

Nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3

NMDA

N-methyl-D-aspartate

NO

Nitric oxide

PS

Presenilin

RANTES

Regulated on activation, normal T cell expressed and secreted

RyR

Ryanodine receptor

TNF-α

Tumor necrosis factor-α

WT

Wild-type

Notes

Acknowledgement

We thank A. Kaupp for technical assistance. A recent in vivo study reports a profound dysregulation of intracellular Ca2+ homeostasis in plaque-associated microglia (Brawek et al. (2014) Impairment of in vivo calcium signaling in amyloid plaque-associated microglia. Acta Neuropathol in press).

References

  1. Abramov AY, Canevari L, Duchen MR (2003) Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J Neurosci 23:5088–5095PubMedGoogle Scholar
  2. Agulhon C, Sun MY, Murphy T, Myers T, Lauderdale K, Fiacco TA (2012) Calcium signaling and gliotransmission in normal vs. reactive astrocytes. Front Pharmacol 3:139PubMedCentralPubMedGoogle Scholar
  3. Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2:734–744PubMedGoogle Scholar
  4. Arispe N, Rojas E, Pollard HB (1993) Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci U S A 90:567–571PubMedCentralPubMedGoogle Scholar
  5. Avignone E, Ulmann L, Levavasseur F, Rassendren F, Audinat E (2008) Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. J Neurosci 28:9133–9144PubMedGoogle Scholar
  6. Bernhardi R von, Tichauer JE, Eugenin J (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112:1099–1114Google Scholar
  7. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529PubMedGoogle Scholar
  8. Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463PubMedCentralPubMedGoogle Scholar
  9. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4:702–710PubMedGoogle Scholar
  10. Bodin P, Burnstock G (1998) Increased release of ATP from endothelial cells during acute inflammation. Inflamm Res 47:351–354PubMedGoogle Scholar
  11. Brawek B, Garaschuk O (2013) Microglial calcium signaling in the adult, aged and diseased brain. Cell Calcium 53:159–169PubMedGoogle Scholar
  12. Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25:7709–7717PubMedGoogle Scholar
  13. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321:1686–1689PubMedGoogle Scholar
  14. Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B, Konnerth A (2012) Critical role of soluble amyloid-beta for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 109:8740–8745PubMedCentralPubMedGoogle Scholar
  15. Carrero I, Gonzalo MR, Martin B, Sanz-Anquela JM, Arevalo-Serrano J, Gonzalo-Ruiz A (2012) Oligomers of beta-amyloid protein (Abeta1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain. Exp Neurol 236:215–227PubMedGoogle Scholar
  16. Chakroborty S, Briggs C, Miller MB, Goussakov I, Schneider C, Kim J, Wicks J, Richardson JC, Conklin V, Cameransi BG, Stutzmann GE (2012a) Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer’s disease. PLoS One 7:e52056PubMedCentralPubMedGoogle Scholar
  17. Chakroborty S, Kim J, Schneider C, Jacobson C, Molgo J, Stutzmann GE (2012b) Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer’s disease mice. J Neurosci 32:8341–8353PubMedCentralPubMedGoogle Scholar
  18. Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK (2008) Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58:871–883PubMedCentralPubMedGoogle Scholar
  19. Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM (2005) Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48:913–922PubMedGoogle Scholar
  20. Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58:42–51PubMedCentralPubMedGoogle Scholar
  21. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758PubMedGoogle Scholar
  22. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL (2007) Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590–11601PubMedGoogle Scholar
  23. Demuro A, Parker I (2013) Cytotoxicity of intracellular abeta42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. J Neurosci 33:3824–3833PubMedCentralPubMedGoogle Scholar
  24. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG (2005) Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280:17294–17300PubMedGoogle Scholar
  25. Di Virgilio F, Ceruti S, Bramanti P, Abbracchio MP (2009) Purinergic signalling in inflammation of the central nervous system. Trends Neurosci 32:79–87PubMedGoogle Scholar
  26. Dineley KT, Hogan D, Zhang WR, Taglialatela G (2007) Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem 88:217–224PubMedCentralPubMedGoogle Scholar
  27. Domercq M, Brambilla L, Pilati E, Marchaland J, Volterra A, Bezzi P (2006) P2Y1 receptor-evoked glutamate exocytosis from astrocytes: control by tumor necrosis factor-alpha and prostaglandins. J Biol Chem 281:30684–30696PubMedGoogle Scholar
  28. Eichhoff G, Brawek B, Garaschuk O (2011) Microglial calcium signal acts as a rapid sensor of single neuron damage in vivo. Biochim Biophys Acta 1813:1014–1024PubMedGoogle Scholar
  29. Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A (2002) Neuroinflammation in Alzheimer’s disease and prion disease. Glia 40:232–239PubMedGoogle Scholar
  30. Färber K, Kettenmann H (2006) Functional role of calcium signals for microglial function. Glia 54:656–665PubMedGoogle Scholar
  31. Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10:241–247PubMedCentralPubMedGoogle Scholar
  32. Galic MA, Riazi K, Pittman QJ (2012) Cytokines and brain excitability. Front Neuroendocrinol 33:116–125PubMedCentralPubMedGoogle Scholar
  33. Grienberger C, Rochefort NL, Adelsberger H, Henning HA, Hill DN, Reichwald J, Staufenbiel M, Konnerth A (2012) Staged decline of neuronal function in vivo in an animal model of Alzheimer’s disease. Nat Commun 3:774PubMedCentralPubMedGoogle Scholar
  34. Grolla AA, Sim JA, Lim D, Rodriguez JJ, Genazzani AA, Verkhratsky A (2013) Amyloid-beta and Alzheimer’s disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. Cell Death Dis 4:e623PubMedCentralPubMedGoogle Scholar
  35. Halassa MM, Haydon PG (2010) Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72:335–355PubMedCentralPubMedGoogle Scholar
  36. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9:857–865PubMedCentralPubMedGoogle Scholar
  37. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedGoogle Scholar
  38. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678PubMedGoogle Scholar
  39. Henneberger C, Papouin T, Oliet SH, Rusakov DA (2010) Long-term potentiation depends on release of D-serine from astrocytes. Nature 463:232–236PubMedCentralPubMedGoogle Scholar
  40. Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, Nakata Y (2000) Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J Neurochem 75:965–972PubMedGoogle Scholar
  41. Hirase H, Qian L, Bartho P, Buzsaki G (2004) Calcium dynamics of cortical astrocytic networks in vivo. PLoS Biol 2:E96PubMedCentralPubMedGoogle Scholar
  42. Hoffmann A, Kann O, Ohlemeyer C, Hanisch UK, Kettenmann H (2003) Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia): suppression of receptor-evoked calcium signaling and control of release function. J Neurosci 23:4410–4419PubMedGoogle Scholar
  43. 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 274:99–102PubMedGoogle Scholar
  44. Ikeda M, Tsuno S, Sugiyama T, Hashimoto A, Yamoto K, Takeuchi K, Kishi H, Mizuguchi H, Kohsaka SI, Yoshioka T (2013) Ca2+ spiking activity caused by the activation of store-operated Ca2+ channels mediates TNF-alpha release from microglial cells under chronic purinergic stimulation. Biochim Biophys Acta 1833:2573–2585PubMedGoogle Scholar
  45. Imura Y, Morizawa Y, Komatsu R, Shibata K, Shinozaki Y, Kasai H, Moriishi K, Moriyama Y, Koizumi S (2013) Microglia release ATP by exocytosis. Glia 61:1320–1330PubMedGoogle Scholar
  46. Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D (1989) Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 24:173–182PubMedGoogle Scholar
  47. Ito E, Oka K, Etcheberrigaray R, Nelson TJ, McPhie DL, Tofel-Grehl B, Gibson GE, Alkon DL (1994) Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease. Proc Natl Acad Sci U S A 91:534–538PubMedCentralPubMedGoogle Scholar
  48. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937PubMedGoogle Scholar
  49. Khachaturian ZS (1994) Calcium hypothesis of Alzheimer’s disease and brain aging. Ann N Y Acad Sci 747:1–11PubMedGoogle Scholar
  50. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446:1091–1095PubMedCentralPubMedGoogle Scholar
  51. Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ (2008) Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59:214–225PubMedCentralPubMedGoogle Scholar
  52. Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ (2009) Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323:1211–1215PubMedCentralPubMedGoogle Scholar
  53. LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3:862–872PubMedGoogle Scholar
  54. Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJ (2012) The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492:123–127PubMedGoogle Scholar
  55. Lee M, Schwab C, McGeer PL (2011) Astrocytes are GABAergic cells that modulate microglial activity. Glia 59:152–165PubMedGoogle Scholar
  56. Lim D, Iyer A, Ronco V, Grolla AA, Canonico PL, Aronica E, Genazzani AA (2013) Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB. Glia 61:1134–1145PubMedGoogle Scholar
  57. Mathiesen C, Brazhe A, Thomsen K, Lauritzen M (2013) Spontaneous calcium waves in Bergman glia increase with age and hypoxia and may reduce tissue oxygen. J Cereb Blood Flow Metab 33:161–169PubMedCentralPubMedGoogle Scholar
  58. Mattson MP (2010) ER calcium and Alzheimer’s disease: in a state of flux. Sci Signal 3:pe10PubMedCentralPubMedGoogle Scholar
  59. Mattson MP, Chan SL (2003) Neuronal and glial calcium signaling in Alzheimer’s disease. Cell Calcium 34:385–397PubMedGoogle Scholar
  60. McGeer PL, McGeer EG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126:479–497PubMedGoogle Scholar
  61. McLarnon JG, Choi HB, Lue LF, Walker DG, Kim SU (2005) Perturbations in calcium-mediated signal transduction in microglia from Alzheimer’s disease patients. J Neurosci Res 81:426–435PubMedGoogle Scholar
  62. McLarnon JG, Ryu JK, Walker DG, Choi HB (2006) Upregulated expression of purinergic P2X7 receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus. J Neuropathol Exp Neurol 65:1090–1097PubMedGoogle Scholar
  63. Medeiros R, LaFerla FM (2013) Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol 239:133–138PubMedGoogle Scholar
  64. Mendez M, Lim G (2003) Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging 20:791–803PubMedGoogle Scholar
  65. Meraz-Rios MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernandez J, Campos-Pena V (2013) Inflammatory process in Alzheimer’s Disease. Front Integr Neurosci 7:59PubMedCentralPubMedGoogle Scholar
  66. Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, Calignon A de, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724Google Scholar
  67. Miller KR, Streit WJ (2007) The effects of aging, injury and disease on microglial function: a case for cellular senescence. Neuron Glia Biol 3:245–253PubMedGoogle Scholar
  68. Min R, Nevian T (2012) Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nat Neurosci 15:746–753PubMedGoogle Scholar
  69. Min R, Santello M, Nevian T (2012) The computational power of astrocyte mediated synaptic plasticity. Front Comput Neurosci 6:93PubMedCentralPubMedGoogle Scholar
  70. Möller T (2002) Calcium signaling in microglial cells. Glia 40:184–194PubMedGoogle Scholar
  71. Muller M, Cardenas C, Mei L, Cheung KH, Foskett JK (2011) Constitutive cAMP response element binding protein (CREB) activation by Alzheimer’s disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci U S A 108:13293–13298PubMedCentralPubMedGoogle Scholar
  72. Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, Horng T (2012) Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A 109:11282–11287PubMedCentralPubMedGoogle Scholar
  73. Navarrete M, Araque A (2010) Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron 68:113–126PubMedGoogle Scholar
  74. Nimmerjahn A (2009) Astrocytes going live: advances and challenges. J Physiol (Lond) 587:1639–1647Google Scholar
  75. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318PubMedGoogle Scholar
  76. 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 Abeta and synaptic dysfunction. Neuron 39:409–421PubMedGoogle Scholar
  77. Ogoshi F, Yin HZ, Kuppumbatti Y, Song B, Amindari S, Weiss JH (2005) Tumor necrosis-factor-alpha (TNF-alpha) induces rapid insertion of Ca2+-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons. Exp Neurol 193:384–393PubMedGoogle Scholar
  78. Oules B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Brechot P, Trebak M, Checler F, Benfenati F, Chami M (2012) Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 32:11820–11834PubMedCentralPubMedGoogle Scholar
  79. Palop JJ, Mucke L (2009) Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 66:435–440PubMedCentralPubMedGoogle Scholar
  80. Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818PubMedCentralPubMedGoogle Scholar
  81. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458PubMedGoogle Scholar
  82. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A (2012) Glial cells in (patho)physiology. J Neurochem 121:4–27PubMedCentralPubMedGoogle Scholar
  83. Parvathenani LK, Tertyshnikova S, Greco CR, Roberts SB, Robertson B, Posmantur R (2003) P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease. J Biol Chem 278:13309–13317PubMedGoogle Scholar
  84. Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A 109:E197–E205PubMedCentralPubMedGoogle Scholar
  85. Peng J, Liang G, Inan S, Wu Z, Joseph DJ, Meng Q, Peng Y, Eckenhoff MF, Wei H (2012) Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett 516:274–279PubMedCentralPubMedGoogle Scholar
  86. Popugaeva E, Bezprozvanny I (2013) Role of endoplasmic reticulum Ca2+ signaling in the pathogenesis of Alzheimer disease. Front Mol Neurosci 6:29PubMedCentralPubMedGoogle Scholar
  87. Qiu C, Kivipelto M, Strauss E von (2009) Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 11:111–128Google Scholar
  88. Querfurth HW, Selkoe DJ (1994) Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 33:4550–4561PubMedGoogle Scholar
  89. Querfurth HW, Jiang J, Geiger JD, Selkoe DJ (1997) Caffeine stimulates amyloid beta-peptide release from beta-amyloid precursor protein-transfected HEK293 cells. J Neurochem 69:1580–1591PubMedGoogle Scholar
  90. Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ (2008) Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci U S A 105:17151–17156PubMedCentralPubMedGoogle Scholar
  91. Rockenstein EM, McConlogue L, Tan H, Power M, Masliah E, Mucke L (1995) Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer’s disease. J Biol Chem 270:28257–28267PubMedGoogle Scholar
  92. Rodgers KM, Hutchinson MR, Northcutt A, Maier SF, Watkins LR, Barth DS (2009) The cortical innate immune response increases local neuronal excitability leading to seizures. Brain 132:2478–2486PubMedCentralPubMedGoogle Scholar
  93. Rossi D, Brambilla L, Valori CF, Crugnola A, Giaccone G, Capobianco R, Mangieri M, Kingston AE, Bloc A, Bezzi P, Volterra A (2005) Defective tumor necrosis factor-alpha-dependent control of astrocyte glutamate release in a transgenic mouse model of Alzheimer disease. J Biol Chem 280:42088–42096PubMedGoogle Scholar
  94. Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer’s disease, role of cytokines. Sci World J 2012:756357Google Scholar
  95. Sama DM, Norris CM (2013) Calcium dysregulation and neuroinflammation: discrete and integrated mechanisms for age-related synaptic dysfunction. Ageing Res Rev 12:982–995PubMedGoogle Scholar
  96. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A 109:E2895–E2903PubMedCentralPubMedGoogle Scholar
  97. Santello M, Volterra A (2012) TNFalpha in synaptic function: switching gears. Trends Neurosci 35:638–647PubMedGoogle Scholar
  98. Schneider I, Reverse D, Dewachter I, Ris L, Caluwaerts N, Kuiperi C, Gilis M, Geerts H, Kretzschmar H, Godaux E, Moechars D, Van Leuven F, Herms J (2001) Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem 276:11539–11544PubMedGoogle Scholar
  99. Schwendele B, Brawek B, Hermes M, Garaschuk O (2012) High resolution in vivo imaging of microglia using a versatile nongenetically-encoded marker. Eur J Immunol 42:2193–2196PubMedGoogle Scholar
  100. Seifert S, Pannell M, Uckert W, Farber K, Kettenmann H (2011) Transmitter- and hormone-activated Ca2+ responses in adult microglia/brain macrophages in situ recorded after viral transduction of a recombinant Ca2+ sensor. Cell Calcium 49:365–375PubMedGoogle Scholar
  101. Smith IF, Hitt B, Green KN, Oddo S, LaFerla FM (2005) Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer’s disease. J Neurochem 94:1711–1718PubMedGoogle Scholar
  102. Snider BJ, Norton J, Coats MA, Chakraverty S, Hou CE, Jervis R, Lendon CL, Goate AM, McKeel DW Jr, Morris JC (2005) Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol 62:1821–1830PubMedGoogle Scholar
  103. Sperling RA, Laviolette PS, O’Keefe K, O’Brien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA (2009) Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63:178–188PubMedCentralPubMedGoogle Scholar
  104. Stutzmann GE (2005) Calcium dysregulation, IP3 signaling, and Alzheimer’s disease. Neuroscientist 11:110–115PubMedGoogle Scholar
  105. Stutzmann GE, Caccamo A, LaFerla FM, Parker I (2004) Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 24:508–513PubMedGoogle Scholar
  106. Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I (2006) Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci 26:5180–5189PubMedGoogle Scholar
  107. Stutzmann GE, Smith I, Caccamo A, Oddo S, Parker I, Laferla F (2007) Enhanced ryanodine-mediated calcium release in mutant PS1-expressing Alzheimer’s mouse models. Ann N Y Acad Sci 1097:265–277PubMedGoogle Scholar
  108. Sun W, McConnell E, Pare JF, Xu Q, Chen M, Peng W, Lovatt D, Han X, Smith Y, Nedergaard M (2013) Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339:197–200PubMedCentralPubMedGoogle Scholar
  109. Taglialatela G, Hogan D, Zhang WR, Dineley KT (2009) Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition. Behav Brain Res 200:95–99PubMedCentralPubMedGoogle Scholar
  110. Takenouchi T, Iwamaru Y, Imamura M, Kato N, Sugama S, Fujita M, Hashimoto M, Sato M, Okada H, Yokoyama T, Mohri S, Kitani H (2007) Prion infection correlates with hypersensitivity of P2X7 nucleotide receptor in a mouse microglial cell line. FEBS Lett 581:3019–3026PubMedGoogle Scholar
  111. Torres A, Wang F, Xu Q, Fujita T, Dobrowolski R, Willecke K, Takano T, Nedergaard M (2012) Extracellular Ca2+ acts as a mediator of communication from neurons to glia. Sci Signal 5:ra8PubMedCentralPubMedGoogle Scholar
  112. Trautmann A (2009) Extracellular ATP in the immune system: more than just a “danger signal”. Sci Signal 2:pe6PubMedGoogle Scholar
  113. Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527PubMedCentralPubMedGoogle Scholar
  114. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126:981–993PubMedCentralPubMedGoogle Scholar
  115. Van Broeckhoven C (1995) Presenilins and Alzheimer disease. Nat Genet 11:230–232PubMedGoogle Scholar
  116. Verderio C, Matteoli M (2011) ATP in neuron-glia bidirectional signalling. Brain Res Rev 66:106–114PubMedGoogle Scholar
  117. Verkhratsky A, Parpura V (2010) Recent advances in (patho)physiology of astroglia. Acta Pharmacol Sin 31:1044–1054PubMedGoogle Scholar
  118. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640PubMedGoogle Scholar
  119. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980PubMedGoogle Scholar
  120. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT (2010) Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 30:2636–2649PubMedCentralPubMedGoogle Scholar
  121. Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2:a006346PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Institute of Physiology IIEberhard Karls University of TübingenTübingenGermany

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