Neurochemical Research

, Volume 42, Issue 8, pp 2230–2245 | Cite as

Post-natal Deletion of Neuronal cAMP Responsive-Element Binding (CREB)-1 Promotes Pro-inflammatory Changes in the Mouse Hippocampus

  • Elisa Marchese
  • Valentina Di Maria
  • Daniela Samengo
  • Giovambattista Pani
  • Fabrizio MichettiEmail author
  • Maria Concetta GelosoEmail author
Original Paper


By taking advantage of a “floxed” conditional CREB mutant mouse (CREB1loxP/loxP), in which postnatal deletion of the Creb gene in the forebrain is driven by the calcium/calmodulin-dependent protein kinase II-α gene (Camk2a) promoter (BCKO mice), we here show that selective disruption of CREB function in adult forebrain neurons results, in adult mice, in morphological alterations at the hippocampal level, including hippocampal shrinkage, reduced somal volume of neurons, microgliosis and mild reactive astrocytosis, mainly involving the CA1 subfield. The huge increase of microglial cells showing a mild activated profile, and the higher percentage of double-stained GFAP/S100B astrocytes, together with the increased expression of S100b mRNA at hippocampal level, suggest the establishment of a sub-inflammatory environment in the hippocampus of BCKO mice compared with age-matched controls. Collectively, the present data link neuron-specific, adult deletion of CREB to hippocampal structural alterations and to the early appearance of neuropathological features closely resembling those occurring in the aged brain. This information may be valuable for the understanding of the role of CREB in neuroinflammatory pathways.


cAMP responsive-element binding (CREB) Neuroinflammation Hippocampus Microglia Astroglia S100B 



This work was supported by funds from Università Cattolica del S. Cuore to F.M. (Linea D3.2 2013). The Authors wish to thank E. Guadagni and D. Bonvissuto for excellent technical support.

Supplementary material

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Supplementary material 1 (DOCX 16 KB)
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Supplementary material 2 (TIF 400 KB)
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Supplementary material 3 (TIF 482 KB)


  1. 1.
    Mayr B, Montminy M (2001) Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 8:599–609CrossRefGoogle Scholar
  2. 2.
    Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861CrossRefPubMedGoogle Scholar
  3. 3.
    Lonze BE, Riccio A, Cohen S, Ginty DD (2002) Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Neuron 34:371–385CrossRefPubMedGoogle Scholar
  4. 4.
    Riccio A, Ahn S, Davenport CM, Blendy JA, Ginty DD (1999) Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286:2358–2361CrossRefPubMedGoogle Scholar
  5. 5.
    Mantamadiotis T, Papalexis N, Dworkin S (2012) CREB signalling in neural stem/progenitor cells: recent developments and the implications for brain tumour biology. Bioessays 34:293–300CrossRefPubMedGoogle Scholar
  6. 6.
    Jancic D, Lopez de Armentia M, Valor LM, Olivares R, Barco A (2009) Inhibition of cAMP response element-binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration. Cereb Cortex 19:2535–2547CrossRefPubMedGoogle Scholar
  7. 7.
    Rudolph D, Tafuri A, Gass P, Hämmerling GJ, Arnold B, Schütz G (1998) Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP response element binding protein. Proc Natl Acad Sci USA 95:4481–4486CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Mantamadiotis T, Lemberger T, Bleckmann SC, Kern H, Kretz O, Martin Villalba A, Tronche F, Kellendonk C, Gau D, Kapfhammer J, Otto C, Schmid W, Schu¨tz G (2002) Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 31:47–54CrossRefPubMedGoogle Scholar
  9. 9.
    Nonaka M (2009) A Janus-like role of CREB protein: enhancement of synaptic property in mature neurons and suppression of synaptogenesis and reduced network synchrony in early development. J Neurosci 29:6389–6391CrossRefPubMedGoogle Scholar
  10. 10.
    Aguado F, Díaz-Ruiz C, Parlato R, Martínez A, Carmona MA, Bleckmann S, Urena JM, Burgaya F, del Río JA, Schutz G, Soriano E (2009) The CREB/CREM transcription factors negatively regulate early synaptogenesis and spontaneous network activity. J Neurosci 29:328–333CrossRefPubMedGoogle Scholar
  11. 11.
    Valor LM, Jancic D, Lujan R, Barco A (2010) Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function. Cell Death Differ 17:1636–1644CrossRefPubMedGoogle Scholar
  12. 12.
    Michaelis EK (2012) Selective Neuronal Vulnerability in the Hippocampus: Relationship to Neurological Diseases and Mechanisms for Differential Sensitivity of Neurons to Stress CHAPTER in The Clinical Neurobiology of the Hippocampus Published in print July 2012, SBN:9780199592388$4Google Scholar
  13. 13.
    Yin JC, Wallach JS, Del Vecchio M, Wilder EL, Zhou H, Quinn WG, Tully T (1994) Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79:49–58CrossRefPubMedGoogle Scholar
  14. 14.
    Yin JC, Del Vecchio M, Zhou H, Tully T (1995) CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances longterm memory in Drosophila. Cell 81:107–115CrossRefPubMedGoogle Scholar
  15. 15.
    Bartsch T (2012) The clinical neurobiology of the Hippocampus. Oxford University Press, OxfordCrossRefGoogle Scholar
  16. 16.
    Bartsch T, Wulff P (2015) The hippocampus in aging and disease: from plasticity to vulnerability. Neuroscience 309:1–16CrossRefPubMedGoogle Scholar
  17. 17.
    Leuner B, Gould E (2010) Structural plasticity and hippocampal function. Annu Rev Psychol 61:C111–C113CrossRefGoogle Scholar
  18. 18.
    McEwen BS (1999) Stress and the aging hippocampus. Front Neuroendocrinol 20:49–70CrossRefPubMedGoogle Scholar
  19. 19.
    Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79:59–68CrossRefPubMedGoogle Scholar
  20. 20.
    Leal SL, Yassa MA (2015) Neurocognitive aging and the hippocampus across species. Trends Neurosci 38:800–812CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fusco S, Ripoli C, Podda MV, Ranieri SC, Leone L, Toietta G, McBurney MW, Schütz G, Riccio A, Grassi C, Galeotti T, Pani G (2012) A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction. Proc Natl Acad Sci USA 109:621–626CrossRefPubMedGoogle Scholar
  22. 22.
    Casanova E, Fehsenfeld S, Mantamadiotis T, Lemberger T, Greiner E, Stewart AF, Schütz G (2001) A CamKIIalpha iCre BAC allows brain-specific gene inactivation. Genesis 31:37–42CrossRefPubMedGoogle Scholar
  23. 23.
    Hummler E, Cole TJ, Blendy JA, Ganss R, Aguzzi A, Schmid W, Beermann F, Schütz G (1994) Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc Natl Acad Sci USA 91:5647–5651CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Altman J, Bayer S (1975) Postnatal development of the hippocampal dentate gyrus under normal and experimental conditions. In: Isaacson RL, Pribram KH (eds) The hippocampus volume 1: structure and development. Plenum Press, New York. ISBN: 978-1-4684-2978-7 (Print) 978-1-4684-2976-3$4(Online)Google Scholar
  25. 25.
    Klausberger T, Marton LF, O’Neill J, Huck JH, Dalezios Y, Fuentealba P et al (2005) Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations. J Neurosci 25:9782–9793CrossRefPubMedGoogle Scholar
  26. 26.
    Donato F, Rompani SB, Caroni P (2013) Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature 504:272–276CrossRefPubMedGoogle Scholar
  27. 27.
    Andrioli A, Alonso-Nanclares L, Arellano JI, DeFelipe J (2007) Quantitative analysis of parvalbumin-immunoreactive cells in the human epileptic hippocampus. Neuroscience 149:131–143CrossRefPubMedGoogle Scholar
  28. 28.
    Cicchetti F, Prensa L, Wu Y, Parent A (2000) Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington’s disease. Brain Res Rev 34:80–101CrossRefPubMedGoogle Scholar
  29. 29.
    Kuruba R, Hattiangady B, Parihar VK, Shuai B, Shetty AK (2011) Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity. PLoS ONE 6:e24493CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Pugliese M, Carrasco JL, Geloso MC, Mascort J, Michetti F, Mahy N (2004) Gamma-aminobutyric acidergic interneuron vulnerability to aging in canine prefrontal cortex. J Neurosci Res 77:913–920CrossRefPubMedGoogle Scholar
  31. 31.
    Paxinos G, Franklin KBJ (2013) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates, vol 1, 4th edn. Elsevier/Academic Press, BostonGoogle Scholar
  32. 32.
    Corvino V, Marchese E, Podda MV, Lattanzi W, Giannetti S, Di Maria V, Cocco S, Grassi C, Michetti F, Geloso MC (2014) The neurogenic effects of exogenous neuropeptide Y: early molecular events and long-lasting effects in the hippocampus of trimethyltin-treated rats. PLoS ONE 9(2):e88294. doi: 10.1371/journal.pone.0088294 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Corvino V, Di Maria V, Marchese E, Lattanzi W, Biamonte F, Michetti F, Geloso MC (2015) Estrogen administration modulates hippocampal GABAergic subpopulations in the hippocampus of trimethyltin-treated rats. Front Cell Neurosci 9:433 doi: 10.3389/fncel.2015.00433 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method 25:402–408CrossRefGoogle Scholar
  35. 35.
    Corvino V, Marchese E, Giannetti S, Lattanzi W, Bonvissuto D, Biamonte F, Mongiovì AM, Michetti F, Geloso MC (2012) The neuroprotective and neurogenic effects of neuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy induced by trimethyltin. J Neurochem 122:415–426CrossRefPubMedGoogle Scholar
  36. 36.
    Gundersen HJG (1988) The nucleator. J Microscopy 151:3–21CrossRefGoogle Scholar
  37. 37.
    Gemmell E, Bosomworth H, Allan L, Hall R, Khundakar A, Oakley AE, Deramecourt V, Polvikoski TM, O’Brien JT, Kalaria RN (2012) Hippocampal neuronal atrophy and cognitive function in delayed poststroke and aging-related dementias. Stroke 43:808–814CrossRefPubMedGoogle Scholar
  38. 38.
    Gundersen H, Jensen E (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263CrossRefPubMedGoogle Scholar
  39. 39.
    Vernon A, Natesan S, Modo M, Kapur S (2011) Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex-vivo and post mortem confirmation. Biol Psychiatry 69:936–944CrossRefPubMedGoogle Scholar
  40. 40.
    Redwine JM, Kosofsky B, Jacobs RE, Games D, Reilly JF, Morrison JH, Young WG, Bloom FE (2003) Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: a magnetic resonance microscopy and stereologic analysis. Proc Natl Acad Sci USA 100:1381–1386CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497CrossRefPubMedGoogle Scholar
  42. 42.
    Sholl D (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87:387PubMedPubMedCentralGoogle Scholar
  43. 43.
    Schoenen J (1982) The dendritic organization of the human spinal cord: the dorsal horn. Neuroscience 7:2057–2087CrossRefPubMedGoogle Scholar
  44. 44.
    Morrison HW, Filosa JA (2013) A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 10:4CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Abercrombie M (1946) Estimation of nuclear population from microtome sections. Anat Rec 94:239–247CrossRefPubMedGoogle Scholar
  46. 46.
    Geloso MC, Vinesi P, Michetti F (1996) Parvalbumin-immunoreactive neurons are not affected by trimethyltin-induced neurodegeneration in the rat hippocampus. Exp Neurol 139:269–277CrossRefPubMedGoogle Scholar
  47. 47.
    Geloso MC, Vinesi P, Michetti F (1997) Calretinin-containing neurons in trimethyltin-induced neurodegeneration in the rat hippocampus: an immunocytochemical study. Exp Neurol 146:67–73CrossRefPubMedGoogle Scholar
  48. 48.
    Geloso MC, Vinesi P, Michetti F (1998) Neuronal subpopulations of developing rat hippocampus containing different calcium-binding proteins behave distinctively in trimethyltin-induced neurodegeneration. Exp Neurol 154:645–653CrossRefPubMedGoogle Scholar
  49. 49.
    Del Tongo C, Carretta D, Fulgenzi G, Catini C, Minciacchi D (2009) Parvalbumin-positive GABAergic interneurons are increased in the dorsal hippocampus of the dystrophic mdx mouse. Acta Neuropathol 118:803–812CrossRefPubMedGoogle Scholar
  50. 50.
    Wong WT (2013) Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Front Cell Neurosci 7:22. doi: 10.3389/fncel.2013.00022 PubMedPubMedCentralGoogle Scholar
  51. 51.
    Graeber MB, Streit WJ, Kiefer R, Schoen SW, Kreutzberg GW (1990) New expression of myelomonocytic antigens by microglia and perivascular cells following lethal motor neurone injury. J Neuroimmunol 27:121–131CrossRefPubMedGoogle Scholar
  52. 52.
    Slepko N, Levi G (1996) Progressive activation of adult microglial cells in vitro. Glia 16:241–246CrossRefPubMedGoogle Scholar
  53. 53.
    Kingham PJ, Cuzner ML, Pocock JM (1999) Apoptotic pathways mobilized in microglia and neurones as a consequence of chromogranin A-induced microglial activation. J Neurochem 73:538–547CrossRefPubMedGoogle Scholar
  54. 54.
    Ogata K, Kosaka T (2002) Structural and quantitative analysis of astrocytes in the mouse hippocampus. Neuroscience 113:221–233CrossRefPubMedGoogle Scholar
  55. 55.
    Michetti F, Corvino V, Geloso MC, Lattanzi W, Bernardini C, Serpero L, Gazzolo D (2012) The S100B protein in biological fluids: more than a lifelong biomarker of brain distress. J Neurochem 120:644–659CrossRefPubMedGoogle Scholar
  56. 56.
    Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623CrossRefPubMedGoogle Scholar
  57. 57.
    Nair A, Vaidya VA (2006) Cyclic AMP response element binding protein and brain-derived neurotrophic factor: molecules that modulate our mood? J Biosci 31:423–434CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Yu H, Chen ZY (2011) The role of BDNF in depression on the basis of its location in the neural circuitry. Acta Pharmacol Sin 32:3–11CrossRefPubMedGoogle Scholar
  59. 59.
    Hollis ER, Tuszynski MH (2011) Neurotrophins: potential therapeutic tools for the treatment of spinal cord injury. Neurother 8:694–703CrossRefGoogle Scholar
  60. 60.
    Zhao X, Chen XQ, Han E, Hu Y, Paik P, Ding Z, Overman J, Lau AL, Shahmoradian SH, Chiu W, Thompson LM, Wu C, Mobley WC (2016) TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease. Proc Natl Acad Sci USA 113:E5655–E5664CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Heckers S, Konradi C (2002) Hippocampal neurons in schizophrenia. J Neural Transm (Vienna) 109:891–905CrossRefGoogle Scholar
  62. 62.
    Stratmann M, Konrad C, Kugel H, Krug A, Schöning S, Ohrmann P, Uhlmann C, Postert C, Suslow T, Heindel W, Arolt V, Kircher T, Dannlowski U (2014) Insular and hippocampal gray matter volume reductions in patients with major depressive disorder. PLoS ONE 9:e102692. doi: 10.1371/journal.pone.0102692 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Rajkowska G, Selemon LD, Goldman-Rakic PS (1998) Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 55:215–224CrossRefPubMedGoogle Scholar
  64. 64.
    Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, Uylings HB, Friedman L, Rajkowska G (2004) Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry 56:640–650CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Gonzalez-Burgos G, Cho RY, Lewis DA (2015) Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry 77:1031–1040CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Pehrson AL, Sanchez C (2015) Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants. Drug Des Devel Ther 9:603–624CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Mueller SG, Schuff N, Yaffe K, Madison C, Miller B, Weiner MW (2010) Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer’s disease. Hum Brain Mapp 31:1339–1347CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Mueller SG, Stables L, Du AT, Schuff N, Truran D, Cashdollar N, Weiner MW (2007) Measurement of hippocampal subfields and age-related changes with high resolution MRI at 4 T. Neurobiol Aging 28:719–726CrossRefPubMedGoogle Scholar
  69. 69.
    Finch CE (1993) Neuron atrophy during aging: programmed or sporadic? Trends Neurosci 16:104–110CrossRefPubMedGoogle Scholar
  70. 70.
    Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20:659–663CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Porte Y, Buhot MC, Mons N (2008) Alteration of CREB phosphorylation and spatial memory deficits in aged 129T2/Sv mice. Neurobiol Aging 29:1533–1546CrossRefPubMedGoogle Scholar
  72. 72.
    Yu XW, Oh MM, Disterhoft JF (2016) CREB, cellular excitability, and cognition: implications for aging. Behav Brain Res S0166-4328(16):30477–30476Google Scholar
  73. 73.
    Luo XG, Ding JQ, Chen SD (2010) Microglia in the aging brain: relevance to neurodegeneration. Mol Neurodegener 5:12. doi: 10.1186/1750-1326-5-12 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Streit WJ (2006) Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci 29:506–510CrossRefPubMedGoogle Scholar
  75. 75.
    Cerbai F, Lana D, Nosi D, Petkova-Kirova P, Zecchi S, Brothers HM, Wenk GL, Giovannini MG (2012) The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus. PLoS ONE 7:e45250CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Luo XG, Chen SD (2012) The changing phenotype of microglia from homeostasis to disease. Transl Neurodegener 1:9. doi: 10.1186/2047-9158-1-9 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318CrossRefPubMedGoogle Scholar
  78. 78.
    Limatola C, Ransohoff RM (2014) Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front Cell Neurosci 8:229CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Sheridan GK, Murphy KJ (2013) Neuron-glia crosstalk in health and disease: fractalkine and CX3CR1 take centre stage. Open Biol 3:130181CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Spruston N, McBain C (2007) Structural and functional properties of hippocampal neurons. In: The hippocampus book. Per Andersen Oxford University Press, Oxford, pp 133–201Google Scholar
  81. 81.
    Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77:10–18CrossRefPubMedGoogle Scholar
  82. 82.
    Norden DM, Godbout JP (2013) Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39:19–34CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J (2015) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 7:124. doi: 10.3389/fnagi.2015.00124 Google Scholar
  84. 84.
    Barrientos RM, Kitt MM, Watkins LR, Maier SF (2015) Neuroinflammation in the normal aging hippocampus. Neuroscience 309:84–99CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Franceschi C (2007) Inflammaging as a major characteristic of old people: can it be prevented or cured? Nutr Rev 65:S173–S176CrossRefPubMedGoogle Scholar
  86. 86.
    Cotrina ML, Nedergaard M (2002) Astrocytes in the aging brain. J Neurosci Res 67:1–10CrossRefPubMedGoogle Scholar
  87. 87.
    Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94:1077–10798CrossRefPubMedGoogle Scholar
  88. 88.
    Griffin WS, Yeralan O, Sheng JG, Boop FA, Mrak RE, Rovnaghi CR, Burnett BA, Feoktistova A, Van Eldik LJ (1995) Overexpression of the neurotrophic cytokine S100 beta in human temporal lobe epilepsy. J Neurochem 65:228–233CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Shapiro LA, Bialowas-McGoey LA, Whitaker-Azmitia PM (2010) Syndrome and Alzheimer’s Disease: studies in an S100B overexpressing mouse model. Cardiovasc Psychiatry Neurol. doi: 10.1155/2010/153657 PubMedPubMedCentralGoogle Scholar
  90. 90.
    Adami C, Sorci G, Blasi E, Agneletti AL, Bistoni F, Donato R (2001) S100B expression in and effects on microglia. Glia 33:131–142CrossRefPubMedGoogle Scholar
  91. 91.
    Bianchi R, Adami C, Giambanco I, Donato R (2007) S100B binding to RAGE in microglia stimulates COX-2 expression. J Leukoc Biol 81:108–101CrossRefPubMedGoogle Scholar
  92. 92.
    Pilegaard K, Ladefoged O (1996) Total number of astrocytes in the molecular layer of the dentate gyrus of rats at different ages. Anal Quant Cytol Histol 18:279–285PubMedGoogle Scholar
  93. 93.
    Morgan TE, Rozovsky I, Goldsmith SK, Stone DJ, Yoshida T et al (1997) Increased transcription of the astrocyte gene GFAP during middle-age is attenuated by food restriction: implications for the role of oxidative stress. Free Radic Biol Med 23:524–528CrossRefPubMedGoogle Scholar
  94. 94.
    Sheng JG, Mrak RE, Rovnaghi CR, Kozlowska E, Van Eldik LJ, Griffin WST (1996) Human brain S100 and S100 mRNA expression increases with age: pathogenic implications for Alzheimer’s disease. Neurobiol Aging 17:359–363CrossRefPubMedGoogle Scholar
  95. 95.
    Nichols NR (1999) Glial responses to steroids as markers of brain aging. J Neurobiol 40:585–601CrossRefPubMedGoogle Scholar
  96. 96.
    Ojo JO, Rezaie P, Gabbott PL, Stewart MG (2015) Impact of age-related neuroglial cell responses on hippocampal deterioration. Front Aging Neurosci 7:57CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Jensen EC (2013) Quantitative analysis of histological staining and fluorescence using ImageJ. Anat Rec (Hoboken) 296: 378–381CrossRefGoogle Scholar
  98. 98.
    Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Elisa Marchese
    • 1
  • Valentina Di Maria
    • 1
  • Daniela Samengo
    • 2
  • Giovambattista Pani
    • 2
  • Fabrizio Michetti
    • 1
    Email author
  • Maria Concetta Geloso
    • 1
    Email author
  1. 1.Institute of Anatomy and Cell BiologyUniversità Cattolica del Sacro CuoreRomeItaly
  2. 2.Institute of General PathologyUniversità Cattolica del Sacro CuoreRomeItaly

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