Age-Dependent Changes in the Activation and Regulation of Microglia

  • Francisca Cornejo
  • Rommy von BernhardiEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 949)


As we age, a large number of physiological and molecular changes affect the normal functioning of cells, tissues, and the organism as a whole. One of the main changes is the establishment of a state of systemic inflammatory activation, which has been termed “inflamm-aging”; a mild chronic inflammation of the aging organism that reduces the ability to generate an efficient response against stressor stimuli. As any other system, the nervous system undergoes these aging-related changes; the neuroinflammatory state depends mainly on the dysregulated activation of microglia, the innate immune cells of the central nervous system (CNS) and the principal producers of reactive oxygen species. As the brain ages, microglia acquire a phenotype that is increasingly inflammatory and cytotoxic, generating a hostile environment for neurons. There is mounting evidence that this process facilitates development of neurodegenerative diseases, for which the greatest risk factor is age. In this chapter, we will review key aging-associated changes occurring in the central nervous system, focusing primarily on the changes that occur in aging microglia, the inflammatory and oxidative stressful environment they establish, and their impaired regulation. In addition, we will discuss the effects of aged microglia on neuronal function and their participation in the development of neurodegenerative pathologies such as Parkinson’s and Alzheimer’s diseases.


Aging Cytokines Microglia Neuroinflammation Neurodegenerative diseases Oxidative stress 



This work was supported by grant FONDECYT 1131025 and fellowship CONICYT 21120013.


  1. Abutbul S, Shapiro J, Szaingurten-Solodkin I, Levy N, Carmy Y, Baron R, Jung S, Monsonego A (2012) TGF-β signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. Glia 60(7):1160–1171. doi: 10.1002/glia.22343 PubMedCrossRefGoogle Scholar
  2. Adler A, Sinha S, Kawahara T, Zhang J, Segal E, Chang H (2007) Motif module map reveals enforcement of aging by continual NF-κB activity. Genes Dev 21(24):3244–3257. doi: 10.1101/gad.1588507 PubMedPubMedCentralCrossRefGoogle Scholar
  3. Arka Subhra G, Vinay T (2010) Telomeres and inflammation: rap1 joins the ends? Cell Cycle 9. doi: 10.4161/cc.9.19.13383 Google Scholar
  4. Balaban R, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120(4):483–495. doi: 10.1016/j.cell.2005.02.001 PubMedCrossRefGoogle Scholar
  5. Balu M, Sangeetha P, Murali G, Panneerselvam C (2005) Age-related oxidative protein damages in central nervous system of rats: modulatory role of grape seed extract. Int J Dev Neurosci 23(6):501–507. doi: 10.1016/j.ijdevneu.2005.06.001 PubMedCrossRefGoogle Scholar
  6. Barrientos R, Sprunger D, Campeau S, Higgins E, Watkins L, Rudy J, Maier S (2003) Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist. Neuroscience 121(4):847–853. doi: 10.1016/S0306-4522(03)00564-5 PubMedCrossRefGoogle Scholar
  7. Barrientos R, Sprunger D, Campeau S, Watkins L, Rudy J, Maier S (2004) BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration. J Neuroimmunol 155(1–2):119–126. doi: 10.1016/j.jneuroim.2004.06.009 PubMedCrossRefGoogle Scholar
  8. Bellinger F, Madamba S, Siggins G (1993) Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Res 628(1–2):227–234. doi: 10.1016/0006-8993(93)90959-Q PubMedCrossRefGoogle Scholar
  9. Berr C, Balansard B, Arnaud J, Roussel A, Alpérovitch A (2000) Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Artériel. J Am Geriatr Soc 48(10):1285–1291PubMedCrossRefGoogle Scholar
  10. Blobe G, Schiemann W, Lodish H (2000) Role of transforming growth factor beta in human disease. New Engl J Med 342(18):1350–1358. doi: 10.1056/NEJM200005043421807 PubMedCrossRefGoogle Scholar
  11. Block M, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69. doi: 10.1038/nrn2038 PubMedCrossRefGoogle Scholar
  12. Boche D, Cunningham C, Docagne F, Scott H, Perry V (2006) TGFbeta1 regulates the inflammatory response during chronic neurodegeneration. Neurobiol Dis 22(3):638–650. doi: 10.1016/j.nbd.2006.01.004 PubMedCrossRefGoogle Scholar
  13. Bye N, Zieba M, Wreford N, Nichols N (2001) Resistance of the dentate gyrus to induced apoptosis during ageing is associated with increases in transforming growth factor-beta1 messenger RNA. Neuroscience 105(4):853–862. doi: 10.1016/S0306-4522(01)00236-6 PubMedCrossRefGoogle Scholar
  14. Calabrese V, Scapagnini G, Ravagna A, Colombrita C, Spadaro F, Butterfield D, Giuffrida Stella A (2004) Increased expression of heat shock proteins in rat brain during aging: relationship with mitochondrial function and glutathione redox state. Mech Ageing Dev 125(4):325–335. doi: 10.1016/j.mad.2004.01.003 PubMedCrossRefGoogle Scholar
  15. Cencioni C, Spallotta F, Martelli F, Valente S, Mai A, Zeiher A, Gaetano C (2013) Oxidative stress and epigenetic regulation in ageing and age-related diseases. Int J Mol Sci 14(9):17643–17663. doi: 10.3390/ijms140917643 PubMedPubMedCentralCrossRefGoogle Scholar
  16. Chen S, Luo D, Streit W, Harrison J (2002) TGF-beta1 upregulates CX3CR1 expression and inhibits fractalkine-stimulated signaling in rat microglia. J Neuroimmunol 133(1–2):46–55PubMedCrossRefGoogle Scholar
  17. Cherry J, Olschowka J, O’Banion M (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98. doi: 10.1186/1742-2094-11-98 PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cho S-H, Chen J, Sayed F, Ward M, Gao F, Nguyen T, Krabbe G, Sohn P, Lo I, Minami S, Devidze N, Zhou Y, Coppola G, Gan L (2015) SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β. J Neurosci 35(2):807–818. doi: 10.1523/JNEUROSCI.2939-14.2015 PubMedPubMedCentralCrossRefGoogle Scholar
  19. Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ (2002) Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 70(3):462–473. doi: 10.1002/jnr.10351 PubMedCrossRefGoogle Scholar
  20. Combrinck M, Perry V, Cunningham C (2002) Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience 112(1):7–11. doi: 10.1016/S0306-4522(02)00030-1 PubMedCrossRefGoogle Scholar
  21. Conde J, Streit W (2006) Effect of aging on the microglial response to peripheral nerve injury. Neurobiol Aging 27(10):1451–1461. doi: 10.1016/j.neurobiolaging.2005.07.012 PubMedCrossRefGoogle Scholar
  22. Cornejo F, von Bernhardi R (2013) Role of scavenger receptors in glia-mediated neuroinflammatory response associated with Alzheimer’s disease. Mediators Inflamm 2013:895651. doi: 10.1155/2013/895651 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Courchesne E, Chisum H, Townsend J, Cowles A, Covington J, Egaas B, Harwood M, Hinds S, Press G (2000) Normal brain development and aging: quantitative analysis at in vivo MR imaging in healthy volunteers. Radiology 216(3):672–682. doi: 10.1148/radiology.216.3.r00au37672 PubMedCrossRefGoogle Scholar
  24. Cunningham A, Murray C, O’Neill L, Lynch M, O’Connor J (1996) Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci Lett 203(1):17–20PubMedCrossRefGoogle Scholar
  25. Cunningham C, Wilcockson D, Campion S, Lunnon K, Perry V (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25(40):9275–9284. doi: 10.1523/JNEUROSCI.2614-05.2005 PubMedCrossRefGoogle Scholar
  26. de Magalhães J, Curado J, Church G (2009) Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25(7):875–881. doi: 10.1093/bioinformatics/btp073 PubMedPubMedCentralCrossRefGoogle Scholar
  27. de Sampaio e Spohr T, Martinez R, da Silva E, Neto V, Gomes F (2002) Neuro-glia interaction effects on GFAP gene: a novel role for transforming growth factor-beta1. Eur J Neurosci 16(11):2059–2069. doi: 10.1046/j.1460-9568.2002.02283.x Google Scholar
  28. Denise CP, Anderson DS, Gary L, Julie LE et al (1996) Mediators of long-term memory performance across the life span. Psychol Aging 11. doi: 10.1037/0882-7974.11.4.621 Google Scholar
  29. Depino A, Alonso M, Ferrari C, del Rey A, Anthony D, Besedovsky H, Medina J, Pitossi F (2004) Learning modulation by endogenous hippocampal IL-1: blockade of endogenous IL-1 facilitates memory formation. Hippocampus 14(4):526–535. doi: 10.1002/hipo.10164 PubMedCrossRefGoogle Scholar
  30. DeWitt D, Perry G, Cohen M, Doller C, Silver J (1998) Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer’s disease. Exp Neurol 149(2):329–340. doi: 10.1006/exnr.1997.6738 PubMedCrossRefGoogle Scholar
  31. Dhandapani K, Brann D (2003) Transforming growth factor-beta: a neuroprotective factor in cerebral ischemia. Cell Biochem Biophys 39(1):13–22. doi: 10.1385/CBB:39:1:13 PubMedCrossRefGoogle Scholar
  32. Dheen S, Jun Y, Yan Z, Tay S, Ling E (2005) Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia. Glia 50(1):21–31. doi: 10.1002/glia.20153 PubMedCrossRefGoogle Scholar
  33. Driscoll I, Davatzikos C, An Y, Wu X, Shen D, Kraut M, Resnick S (2009) Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. Neurology 72(22):1906–1913. doi: 10.1212/WNL.0b013e3181a82634 PubMedPubMedCentralCrossRefGoogle Scholar
  34. Dröge W, Schipper H (2007) Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 6(3):361–370. doi: 10.1111/j.1474-9726.2007.00294.x PubMedPubMedCentralCrossRefGoogle Scholar
  35. Erraji-Benchekroun L, Underwood M, Arango V, Galfalvy H, Pavlidis P, Smyrniotopoulos P, Mann J, Sibille E (2005) Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biol Psychiatry 57(5):549–558. doi: 10.1016/j.biopsych.2004.10.034 PubMedCrossRefGoogle Scholar
  36. Faith MG-D, Naftali R (2003) Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study. Neuropsychologia 41. doi: 10.1016/S0028-3932(03)00129-5 Google Scholar
  37. Flanary B, Streit W (2004) Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45(1):75–88. doi: 10.1002/glia.10301 PubMedCrossRefGoogle Scholar
  38. Flanary B, Sammons N, Nguyen C, Walker D, Streit W (2007) Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res 10(1):61–74. doi: 10.1089/rej.2006.9096 PubMedCrossRefGoogle Scholar
  39. Floden A, Combs C (2011) Microglia demonstrate age-dependent interaction with amyloid-β fibrils. J Alzheimers Dis 25(2):279–293. doi: 10.3233/JAD-2011-101014 PubMedPubMedCentralGoogle Scholar
  40. Forster M, Dubey A, Dawson K, Stutts W, Lal H, Sohal R (1996) Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Nat Acad Sci USA 93(10):4765–4769. doi: 10.1073/pnas.93.10.4765 PubMedPubMedCentralCrossRefGoogle Scholar
  41. Fraga C, Shigenaga M, Park J, Degan P, Ames B (1990) Oxidative damage to DNA during aging: 8-hydroxy-2′-deoxyguanosine in rat organ DNA and urine. Proc Nat Acad Sci USA 87(12):4533–4537. doi: 10.1073/pnas.87.12.4533 PubMedPubMedCentralCrossRefGoogle Scholar
  42. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254. doi: 10.1111/j.1749-6632.2000.tb06651.x PubMedCrossRefGoogle Scholar
  43. Frank M, Barrientos R, Biedenkapp J, Rudy J, Watkins L, Maier S (2006) mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging 27(5):717–722. doi: 10.1016/j.neurobiolaging.2005.03.013 PubMedCrossRefGoogle Scholar
  44. Fraser H, Khaitovich P, Plotkin J, Pääbo S, Eisen M (2005) Aging and gene expression in the primate brain. PLoS Biol 3(9). doi: 10.1371/journal.pbio.0030274 Google Scholar
  45. Frenkel D, Wilkinson K, Zhao L, Hickman S, Means T, Puckett L, Farfara D, Kingery N, Weiner H, El Khoury J (2013) Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 4:2030. doi: 10.1038/ncomms3030 PubMedPubMedCentralCrossRefGoogle Scholar
  46. Friedrich MJ (2014) Researchers probe the aging brain in health and disease. JAMA 311(3):231–232. doi: 10.1001/jama.2013.284609 PubMedCrossRefGoogle Scholar
  47. Ge Y, Grossman R, Babb J, Rabin M, Mannon L, Kolson D (2002) Age-related total gray matter and white matter changes in normal adult brain. Part I: volumetric MR imaging analysis. AJNR Am J Neuroradiol 23(8):1327–1333PubMedGoogle Scholar
  48. Gefen T, Peterson M, Papastefan S, Martersteck A, Whitney K, Rademaker A, Bigio E, Weintraub S, Rogalski E, Mesulam MM, Geula C (2015) Morphometric and histologic substrates of cingulate integrity in elders with exceptional memory capacity. J Neurosci 35(4):1781–1791. doi: 10.1523/JNEUROSCI.2998-14.2015 PubMedPubMedCentralCrossRefGoogle Scholar
  49. Geula C, Wu C, Saroff D, Lorenzo A, Yuan M, Yankner B (1998) Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med 4(7):827–831. doi: 10.1038/nm0798-827 PubMedCrossRefGoogle Scholar
  50. Godbout J, Chen J, Abraham J, Richwine A, Berg B, Kelley K, Johnson R (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19(10):1329–1331. doi: 10.1096/fj.05-3776fje PubMedGoogle Scholar
  51. Gonzalez P, Machado I, Vilcaes A, Caruso C, Roth G, Schiöth H, Lasaga M, Scimonelli T (2013) Molecular mechanisms involved in interleukin 1-beta (IL-1β)-induced memory impairment. Modulation by alpha-melanocyte-stimulating hormone (α-MSH). Brain Behav Immun 34:141–150. doi: 10.1016/j.bbi.2013.08.007 PubMedCrossRefGoogle Scholar
  52. Good C, Johnsrude I, Ashburner J, Henson R, Friston K, Frackowiak R (2001) A voxel-based morphometric study of ageing in 465 normal adult human brains. NeuroImage 14(1 Pt 1):21–36. doi: 10.1006/nimg.2001.0786 PubMedCrossRefGoogle Scholar
  53. Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, Yirmiya R (2008) Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry 13(7):717–728. doi: 10.1038/ PubMedCrossRefGoogle Scholar
  54. Gravina S, Vijg J (2010) Epigenetic factors in aging and longevity. Pflugers Arch 459(2):247–258. doi: 10.1007/s00424-009-0730-7 PubMedCrossRefGoogle Scholar
  55. Griffin R, Nally R, Nolan Y, McCartney Y, Linden J, Lynch M (2006) The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem 99(4):1263–1272. doi: 10.1111/j.1471-4159.2006.04165.x PubMedCrossRefGoogle Scholar
  56. Gupta A, Hasan M, Chander R, Kapoor N (1991) Age-related elevation of lipid peroxidation products: diminution of superoxide dismutase activity in the central nervous system of rats. Gerontology 37(6):305–309. doi: 10.1159/000213277 PubMedCrossRefGoogle Scholar
  57. Handattu S, Garber D, Monroe C, van Groen T, Kadish I, Nayyar G, Cao D, Palgunachari M, Li L, Anantharamaiah G (2009) Oral apolipoprotein A-I mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer’s disease. Neurobiol Dis 34(3):525–534. doi: 10.1016/j.nbd.2009.03.007 PubMedCrossRefGoogle Scholar
  58. Handattu S, Monroe C, Nayyar G (2013) In vivo and in vitro effects of an apolipoprotein E mimetic peptide on amyloid-β pathology. J Alzheimers Dis 36(2):335–347PubMedPubMedCentralGoogle Scholar
  59. Hanisch U-K, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394. doi: 10.1038/nn1997 PubMedCrossRefGoogle Scholar
  60. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300. doi: 10.1016/0921-8734(92)90030-S PubMedCrossRefGoogle Scholar
  61. Hart A, Wyttenbach A, Perry V, Teeling J (2012) Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav Immun 26(5):754–765. doi: 10.1016/j.bbi.2011.11.006 PubMedPubMedCentralCrossRefGoogle Scholar
  62. Head D, Buckner R, Shimony J, Williams L, Akbudak E, Conturo T, McAvoy M, Morris J, Snyder A (2004) Differential vulnerability of anterior white matter in nondemented aging with minimal acceleration in dementia of the Alzheimer type: evidence from diffusion tensor imaging. Cereb Cortex 14(4):410–423. doi: 10.1093/cercor/bhh003 PubMedCrossRefGoogle Scholar
  63. Hefendehl J, Neher J, Sühs R, Kohsaka S, Skodras A, Jucker M (2014) Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13(1):60–69. doi: 10.1111/acel.12149 PubMedCrossRefGoogle Scholar
  64. Helenius M, Hänninen M, Lehtinen S, Salminen A (1996) Changes associated with aging and replicative senescence in the regulation of transcription factor nuclear factor-κB. Biochem J 318(Pt 2):603–608PubMedPubMedCentralCrossRefGoogle Scholar
  65. Henry C, Huang Y, Wynne A, Godbout J (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 23(3):309–317. doi: 10.1016/j.bbi.2008.09.002 PubMedCrossRefGoogle Scholar
  66. Herrera-Molina R, von Bernhardi R (2005) Transforming growth factor-beta 1 produced by hippocampal cells modulates microglial reactivity in culture. Neurobiol Dis 19(1–2):229–236. doi: 10.1016/j.nbd.2005.01.003 PubMedCrossRefGoogle Scholar
  67. Hickman S, Allison E, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28(33):8354–8360. doi: 10.1523/JNEUROSCI.0616-08.2008 PubMedPubMedCentralCrossRefGoogle Scholar
  68. Hickman S, Kingery N, Ohsumi T, Borowsky M, L-C Wang, Means T, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16(12):1896–1905. doi: 10.1038/nn.3554 PubMedPubMedCentralCrossRefGoogle Scholar
  69. Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14(10). doi: 10.1186/gb-2013-14-10-r115 Google Scholar
  70. Hsieh T-C, Lin W-Y, Ding H-J, Sun S-S, Wu Y-C, Yen K-Y, Kao C-H (2012) Sex- and age-related differences in brain FDG metabolism of healthy adults: an SPM analysis. J Neuroimaging 22(1):21–27. doi: 10.1111/j.1552-6569.2010.00543.x PubMedCrossRefGoogle Scholar
  71. Hudetz J, Iqbal Z, Gandhi S, Patterson K, Byrne A, Hudetz A, Pagel P, Warltier D (2009) Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand 53(7):864–872. doi: 10.1111/j.1399-6576.2009.01978.x PubMedCrossRefGoogle Scholar
  72. Hultsch D (1998) Memory change in the aged. Cambridge University PressGoogle Scholar
  73. Ii M, Sunamoto M, Ohnishi K, Ichimori Y (1996) beta-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity. Brain Res 720(1–2):93–100. doi: 10.1016/0006-8993(96)00156-4 PubMedCrossRefGoogle Scholar
  74. Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 106(6):518–526. doi: 10.1007/s00401-003-0766-2 PubMedCrossRefGoogle Scholar
  75. Janeway C, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216. doi: 10.1146/annurev.immunol.20.083001.084359 PubMedCrossRefGoogle Scholar
  76. Jurk D, Wilson C, Passos J, Oakley F, Correia-Melo C, Greaves L, Saretzki G, Fox C, Lawless C, Anderson R, Hewitt G, Pender S, Fullard N, Nelson G, Mann J, van de Sluis B, Mann D, von Zglinicki T (2014) Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun 2:4172. doi: 10.1038/ncomms5172 PubMedPubMedCentralCrossRefGoogle Scholar
  77. Kalpouzos G, Chételat G, Baron J-C, Landeau B, Mevel K, Godeau C, Barré L, Constans J-M, Viader F, Eustache F, Desgranges B (2009) Voxel-based mapping of brain gray matter volume and glucose metabolism profiles in normal aging. Neurobiol Aging 30(1):112–124. doi: 10.1016/j.neurobiolaging.2007.05.019 PubMedCrossRefGoogle Scholar
  78. Kim W, Mohney R, Wilson B, Jeohn G, Liu B, Hong J (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci 20(16):6309–6316PubMedGoogle Scholar
  79. Kochunov P, Ramage A, Lancaster J, Robin D, Narayana S, Coyle T, Royall D, Fox P (2009) Loss of cerebral white matter structural integrity tracks the gray matter metabolic decline in normal aging. NeuroImage 45(1):17–28. doi: 10.1016/j.neuroimage.2008.11.010 PubMedCrossRefGoogle Scholar
  80. Larbi A, Franceschi C, Mazzatti D, Solana R, Wikby A, Pawelec G (2008) Aging of the immune system as a prognostic factor for human longevity. Physiology (Bethesda) 23:64–74. doi: 10.1152/physiol.00040.2007 CrossRefGoogle Scholar
  81. Lee C, Weindruch R, Prolla T (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25(3):294–297. doi: 10.1038/77046 PubMedCrossRefGoogle Scholar
  82. Letiembre M, Hao W, Liu Y, Walter S, Mihaljevic I, Rivest S, Hartmann T, Fassbender K (2007) Innate immune receptor expression in normal brain aging. Neuroscience 146(1):248–254. doi: 10.1016/j.neuroscience.2007.01.004 PubMedCrossRefGoogle Scholar
  83. Lombard D, Chua K, Mostoslavsky R, Franco S, Gostissa M, Alt F (2005) DNA repair, genome stability, and aging. Cell 120(4):497–512. doi: 10.1016/j.cell.2005.01.028 PubMedCrossRefGoogle Scholar
  84. López-Otín C, Blasco M, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217. doi: 10.1016/j.cell.2013.05.039 PubMedPubMedCentralCrossRefGoogle Scholar
  85. Lu T, Pan Y, Kao S-Y, Li C, Kohane I, Chan J, Yankner B (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429(6994):883–891. doi: 10.1038/nature02661 PubMedCrossRefGoogle Scholar
  86. Lucin K, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64(1):110–122. doi: 10.1016/j.neuron.2009.08.039 PubMedPubMedCentralCrossRefGoogle Scholar
  87. Lukiw WJ (2004) Gene expression profiling in fetal, aged, and Alzheimer hippocampus: a continuum of stress-related signaling. Neurochem Res 29(6):1287–1297PubMedCrossRefGoogle Scholar
  88. Lynch A, Loane D, Minogue A, Clarke R, Kilroy D, Nally R, Roche O, O’Connell F, Lynch M (2007) Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol Aging 28(6):845–855. doi: 10.1016/j.neurobiolaging.2006.04.006 PubMedCrossRefGoogle Scholar
  89. Maher F, Clarke R, Kelly A, Nally R, Lynch M (2006) Interaction between interferon gamma and insulin-like growth factor-1 in hippocampus impacts on the ability of rats to sustain long-term potentiation. J Neurochem 96(6):1560–1571. doi: 10.1111/j.1471-4159.2006.03664.x PubMedCrossRefGoogle Scholar
  90. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677–686. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  91. Mawuenyega K, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris J, Yarasheski K, Bateman R (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330(6012):1774. doi: 10.1126/science.1197623 PubMedPubMedCentralCrossRefGoogle Scholar
  92. McCoy M, Martinez T, Ruhn K, Szymkowski D, Smith C, Botterman B, Tansey K, Tansey M (2006) Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J Neurosci 26(37):9365–9375. doi: 10.1523/JNEUROSCI.1504-06.2006 PubMedPubMedCentralCrossRefGoogle Scholar
  93. McGeer P, McGeer E (2002) Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26(4):459–470. doi: 10.1002/mus.10191 PubMedCrossRefGoogle Scholar
  94. McGeer P, Itagaki S, Tago H, McGeer E (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79(1–2):195–200. doi: 10.1016/0304-3940(87)90696-3 PubMedCrossRefGoogle Scholar
  95. McGeer P, Itagaki S, Boyes B, McGeer E (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–1291PubMedCrossRefGoogle Scholar
  96. Meda L, Cassatella M, Szendrei G, Otvos L, Baron P, Villalba M, Ferrari D, Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374(6523):647–650. doi: 10.1038/374647a0 PubMedCrossRefGoogle Scholar
  97. Mittaud P, Labourdette G, Zingg H, Guenot-Di Scala D (2002) Neurons modulate oxytocin receptor expression in rat cultured astrocytes: involvement of TGF-beta and membrane components. Glia 37(2):169–177. doi: 10.1002/glia.10029 PubMedCrossRefGoogle Scholar
  98. Moraes C, Santos G, Spohr T, D’Avila J, Lima F, Benjamim C, Bozza F, Gomes F (2014) Activated Microglia-Induced Deficits in Excitatory Synapses Through IL-1β: Implications for Cognitive Impairment in Sepsis. Mol Neurobiol. doi: 10.1007/s12035-014-8868-5 PubMedGoogle Scholar
  99. Mosher K, Wyss-Coray T (2014) Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol 88(4):594–604. doi: 10.1016/j.bcp.2014.01.008 PubMedPubMedCentralCrossRefGoogle Scholar
  100. Mount M, Lira A, Grimes D, Smith P, Faucher S, Slack R, Anisman H, Hayley S, Park D (2007) Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. J Neurosci 27(12):3328–3337. doi: 10.1523/JNEUROSCI.5321-06.2007 PubMedCrossRefGoogle Scholar
  101. Murgas P, Cornejo F, Merino G, von Bernhardi R (2014) SR-A regulates the inflammatory activation of astrocytes. Neurotox Res 25(1):68–80. doi: 10.1007/s12640-013-9432-1 PubMedCrossRefGoogle Scholar
  102. Navarro A, Gomez C, López-Cepero J, Boveris A (2004) Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol Regul Integr Comp Physiol 286(3):11. doi: 10.1152/ajpregu.00208.2003 CrossRefGoogle Scholar
  103. Nguyen M, Julien J-P, Rivest S (2002) Innate immunity: the missing link in neuroprotection and neurodegeneration? Nature Rev Neurosci 3(3):216–227. doi: 10.1038/nrn752 CrossRefGoogle Scholar
  104. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. doi: 10.1126/science.1110647 PubMedCrossRefGoogle Scholar
  105. Nixon R, Mathews P, Cataldo A (2001) The neuronal endosomal-lysosomal system in Alzheimer’s disease. J Alzheimers Dis 3(1):97–107PubMedGoogle Scholar
  106. Njie E, Boelen E, Stassen F, Steinbusch H, Borchelt D, Streit W (2012) Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 33(1):195.e1–195.e12. doi: 10.1016/j.neurobiolaging.2010.05.008 CrossRefGoogle Scholar
  107. Park D, Lautenschlager G, Hedden T, Davidson N, Smith A, Smith P (2002) Models of visuospatial and verbal memory across the adult life span. Psychol Aging 17(2):299–320PubMedCrossRefGoogle Scholar
  108. Perkins A, Hendrie H, Callahan C, Gao S, Unverzagt F, Xu Y, Hall K, Hui S (1999) Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am J Epidemiol 150(1):37–44. doi: 10.1093/oxfordjournals.aje.a009915 PubMedCrossRefGoogle Scholar
  109. Perluigi M, Swomley A, Butterfield D (2014) Redox proteomics and the dynamic molecular landscape of the aging brain. Ageing Res Rev 13:75–89. doi: 10.1016/j.arr.2013.12.005 PubMedCrossRefGoogle Scholar
  110. Perrig W, Perrig P, Stähelin H (1997) The relation between antioxidants and memory performance in the old and very old. J Am Geriatr Soc 45(6):718–724PubMedCrossRefGoogle Scholar
  111. Perry V, Matyszak M, Fearn S (1993) Altered antigen expression of microglia in the aged rodent CNS. Glia 7(1):60–67. doi: 10.1002/glia.440070111 PubMedCrossRefGoogle Scholar
  112. Perry V, Cunningham C, Boche D (2002) Atypical inflammation in the central nervous system in prion disease. Curr Opin Neurol 15(3):349–354. doi: 10.1097/00019052-200206000-00020 PubMedCrossRefGoogle Scholar
  113. Pocock J, Kettenmann H (2007) Neurotransmitter receptors on microglia. Trends Neurosci 30(10):527–535. doi: 10.1016/j.tins.2007.07.007 PubMedCrossRefGoogle Scholar
  114. Pruitt K, Zinn R, Ohm J, McGarvey K, Kang S-HL, Watkins D, Herman J, Baylin S (2006) Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2(3). doi: 10.1371/journal.pgen.0020040 Google Scholar
  115. Qin L, Liu Y, Cooper C, Liu B, Wilson B, Hong J-S (2002) Microglia enhance beta-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species. J Neurochem 83(4):973–983. doi: 10.1046/j.1471-4159.2002.01210.x PubMedCrossRefGoogle Scholar
  116. Rachal Pugh C, Fleshner M, Watkins L, Maier S, Rudy J (2001) The immune system and memory consolidation: a role for the cytokine IL-1β. Neurosci Biobehav Rev 25(1):29–41PubMedCrossRefGoogle Scholar
  117. Ramírez G, Rey S, von Bernhardi R (2008) Proinflammatory stimuli are needed for induction of microglial cell-mediated AβPP_{244-C} and Aβ-neurotoxicity in hippocampal cultures. J Alzheimers Dis 15(1):45–59PubMedGoogle Scholar
  118. Raz N, Lindenberger U, Rodrigue K, Kennedy K, Head D, Williamson A, Dahle C, Gerstorf D, Acker J (2005) Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 15(11):1676–1689. doi: 10.1093/cercor/bhi044 PubMedCrossRefGoogle Scholar
  119. Richter C, Park J, Ames B (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Nat Acad Sci USA 85(17):6465–6467. doi: 10.1073/pnas.85.17.6465 PubMedPubMedCentralCrossRefGoogle Scholar
  120. Rodrigue K, Raz N (2004) Shrinkage of the entorhinal cortex over five years predicts memory performance in healthy adults. J Neurosci 24(4):956–963. doi: 10.1523/JNEUROSCI.4166-03.2004 PubMedCrossRefGoogle Scholar
  121. Rodrigues Siqueira I, Fochesatto C, da Silva Torres I, Dalmaz C, Alexandre Netto C (2005) Aging affects oxidative state in hippocampus, hypothalamus and adrenal glands of Wistar rats. Life Sci 78(3):271–278. doi: 10.1016/j.lfs.2005.04.044 PubMedCrossRefGoogle Scholar
  122. Rogers J, Luber-Narod J, Styren S, Civin W (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9(4):339–349. doi: 10.1016/S0197-4580(88)80079-4 PubMedCrossRefGoogle Scholar
  123. Rogers J, Strohmeyer R, Kovelowski C, Li R (2002) Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40(2):260–269. doi: 10.1002/glia.10153 PubMedCrossRefGoogle Scholar
  124. Rosen A, Prull M, Gabrieli J, Stoub T, O’Hara R, Friedman L, Yesavage J, deToledo-Morrell L (2003) Differential associations between entorhinal and hippocampal volumes and memory performance in older adults. Behav Neurosci 117(6):1150–1160. doi: 10.1037/0735-7044.117.6.1150 PubMedCrossRefGoogle Scholar
  125. Ross KR, Corey DA, Dunn JM, Kelley TJ (2007) SMAD3 expression is regulated by mitogen-activated protein kinase kinase-1 in epithelial and smooth muscle cells. Cell Signal 19(5):923–931. doi: 10.1016/j.cellsig.2006.11.008 PubMedCrossRefGoogle Scholar
  126. Rozovsky I, Finch C, Morgan T (1998) Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation. Neurobiol Aging 19(1):97–103. doi: 10.1016/S0197-4580(97)00169-3 PubMedCrossRefGoogle Scholar
  127. Salat D, Buckner R, Snyder A, Greve D, Desikan R, Busa E, Morris J, Dale A, Fischl B (2004) Thinning of the cerebral cortex in aging. Cereb Cortex 14(7):721–730. doi: 10.1093/cercor/bhh032 PubMedCrossRefGoogle Scholar
  128. Sapp E, Kegel K, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, Bhide P, Vonsattel J, DiFiglia M (2001) Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol 60(2):161–172PubMedCrossRefGoogle Scholar
  129. Schmierer B, Hill CS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8(12):970–982. doi: 10.1038/nrm2297 PubMedCrossRefGoogle Scholar
  130. Schofield E, Kersaitis C, Shepherd C, Kril J, Halliday G (2003) Severity of gliosis in Pick’s disease and frontotemporal lobar degeneration: tau-positive glia differentiate these disorders. Brain 126(Pt 4):827–840. doi: 10.1093/brain/awg085 PubMedCrossRefGoogle Scholar
  131. Schuitemaker A, van der Doef T, Boellaard R, van der Flier W, Yaqub M, Windhorst A, Barkhof F, Jonker C, Kloet R, Lammertsma A, Scheltens P, van Berckel B (2012) Microglial activation in healthy aging. Neurobiol Aging 33(6):1067–1072. doi: 10.1016/j.neurobiolaging.2010.09.016 PubMedCrossRefGoogle Scholar
  132. Selnes O, Grega M, Borowicz Jr L, Royall R, McKhann G, Baumgartner W (2003) Cognitive changes with coronary artery disease: a prospective study of coronary artery bypass graft patients and nonsurgical controls. Ann Thorac Surg 75(5):1377–1386Google Scholar
  133. Shapira-Lichter I, Beilin B, Ofek K, Bessler H, Gruberger M, Shavit Y, Seror D, Grinevich G, Posner E, Reichenberg A, Soreq H, Yirmiya R (2008) Cytokines and cholinergic signals co-modulate surgical stress-induced changes in mood and memory. Brain Behav Immun 22(3):388–398. doi: 10.1016/j.bbi.2007.09.006 PubMedCrossRefGoogle Scholar
  134. Sheng J, Mrak R, Griffin W (1998) Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol 95(3):229–234PubMedCrossRefGoogle Scholar
  135. Shigenaga M, Hagen T, Ames B (1994) Oxidative damage and mitochondrial decay in aging. Proc Nat Acad Sci USA 91(23):10771–10778. doi: 10.1073/pnas.91.23.10771 PubMedPubMedCentralCrossRefGoogle Scholar
  136. Shock N, Greulich R, Costa P, Andres R, Lakatta E, Arenberg D, Tobin J (1984) Normal human aging: the baltimore longitudinal study of aging. US Department of Health and Human Services, Baltimore, USAGoogle Scholar
  137. Sierra A, Gottfried-Blackmore A, McEwen B, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55(4):412–424. doi: 10.1002/glia.20468 PubMedCrossRefGoogle Scholar
  138. Singh T, Newman A (2011) Inflammatory markers in population studies of aging. Ageing Res Rev 10(3):319–329. doi: 10.1016/j.arr.2010.11.002 PubMedCrossRefGoogle Scholar
  139. Sopper S, Demuth M, Stahl-Hennig C, Hunsmann G, Plesker R, Coulibaly C, Czub S, Ceska M, Koutsilieri E, Riederer P, Brinkmann R, Katz M, ter Meulen V (1996) The effect of simian immunodeficiency virus infection in vitro and in vivo on the cytokine production of isolated microglia and peripheral macrophages from rhesus monkey. Virology 220(2):320–329. doi: 10.1006/viro.1996.0320 PubMedCrossRefGoogle Scholar
  140. Sriram K, Matheson J, Benkovic S, Miller D, Luster M, O’Callaghan J (2002) Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson’s disease. FASEB J 16(11):1474–1476. doi: 10.1096/fj.02-0216fje PubMedGoogle Scholar
  141. Takeuchi H, Wang J, Kawanokuchi J, Mitsuma N, Mizuno T, Suzumura A (2006) Interferon-gamma induces microglial-activation-induced cell death: a hypothetical mechanism of relapse and remission in multiple sclerosis. Neurobiol Dis 22(1):33–39. doi: 10.1016/j.nbd.2005.09.014 PubMedCrossRefGoogle Scholar
  142. Tang Y, Li T, Li J, Yang J, Liu H, Zhang X, Le W (2014) Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease. Cell Death Differ 21(3):369–380. doi: 10.1038/cdd.2013.159 PubMedCrossRefGoogle Scholar
  143. Teo H, Ghosh S, Luesch H, Ghosh A, Wong E, Malik N, Orth A, de Jesus P, Perry A, Oliver J, Tran N, Speiser L, Wong M, Saez E, Schultz P, Chanda S, Verma I, Tergaonkar V (2010) Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. Nat Cell Biol 12(8):758–767. doi: 10.1038/ncb2080 PubMedCrossRefGoogle Scholar
  144. Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can J, Lin A, Crews L, Tremblay P, Mathews P, Mucke L, Masliah E, Wyss-Coray T (2006) Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer’s pathology. J Clin Invest 116(11):3060–3069. doi: 10.1172/JCI27341 PubMedPubMedCentralCrossRefGoogle Scholar
  145. Thakur M, Kanungo M (1981) Methylation of chromosomal proteins and DNA of rat brain and its modulation by estradiol and calcium during aging. Exp Geront 16(4):331–336. doi: 10.1016/0531-5565(81)90052-8 CrossRefGoogle Scholar
  146. Tian L, Cai Q, Wei H (1998) Alterations of antioxidant enzymes and oxidative damage to macromolecules in different organs of rats during aging. Free Radic Biol Med 24(9):1477–1484PubMedCrossRefGoogle Scholar
  147. Tichauer J, von Bernhardi R (2012) Transforming growth factor-β stimulates β amyloid uptake by microglia through Smad3-dependent mechanisms. J Neurosci Res 90(10):1970–1980. doi: 10.1002/jnr.23082 PubMedCrossRefGoogle Scholar
  148. Tichauer J, Flores B, Soler B, Eugenín-von Bernhardi L, Ramírez G, von Bernhardi R (2014) Age-dependent changes on TGFβ1 Smad3 pathway modify the pattern of microglial cell activation. Brain Behav Immun 37:187–196. doi: 10.1016/j.bbi.2013.12.018 PubMedCrossRefGoogle Scholar
  149. Tremblay M-È, Zettel M, Ison J, Allen P, Majewska A (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60(4):541–558. doi: 10.1002/glia.22287 PubMedPubMedCentralCrossRefGoogle Scholar
  150. Tsurumi A, Li W (2012) Global heterochromatin loss: a unifying theory of aging? Epigenetics 7(7):680–688. doi: 10.4161/epi.20540 PubMedPubMedCentralCrossRefGoogle Scholar
  151. Ueberham U, Ueberham E, Gruschka H, Arendt T (2006) Altered subcellular location of phosphorylated Smads in Alzheimer’s disease. Eur J Neurosci 24(8):2327–2334. doi: 10.1111/j.1460-9568.2006.05109.x PubMedCrossRefGoogle Scholar
  152. VanGuilder H, Bixler G, Brucklacher R, Farley J, Yan H, Warrington J, Sonntag W, Freeman W (2011) Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J Neuroinflammation 8:138. doi: 10.1186/1742-2094-8-138 PubMedPubMedCentralCrossRefGoogle Scholar
  153. Vanyushin B, Nemirovsky L, Klimenko V, Vasiliev V, Belozersky A (1973) The 5-methylcytosine in DNA of rats. Tissue and age specificity and the changes induced by hydrocortisone and other agents. Gerontologia 19(3):138–152PubMedCrossRefGoogle Scholar
  154. Vaughan D, Peters A (1974) Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study. J Neurocytol 3(4):405–429. doi: 10.1007/BF01098730 PubMedCrossRefGoogle Scholar
  155. Vaupel JW (2010) Biodemography of human ageing. Nature. doi: 10.1038/nature08984 Google Scholar
  156. von Bernhardi R (2007) Glial cell dysregulation: a new perspective on Alzheimer disease. Neurotox Res 12(4):215–232. doi: 10.1007/BF03033906 CrossRefGoogle Scholar
  157. von Bernhardi R, Eugenín J (2004) Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors. Brain Res 1025(1–2):186–193. doi: 10.1016/j.brainres.2004.07.084 CrossRefGoogle Scholar
  158. von Bernhardi R, Eugenin J (2012) Alzheimer’s disease: redox dysregulation as a common denominator for diverse pathogenic mechanisms. Antioxid Redox Signal 16(9):974–1031. doi: 10.1089/ars.2011.4082 CrossRefGoogle Scholar
  159. von Bernhardi R, Ramirez G (2001) Microglia-astrocyte interaction in Alzheimer’s disease: friends or foes for the nervous system? Biol Res 34(2):123–128. doi: 10.4067/S0716-97602001000200017 Google Scholar
  160. von Bernhardi R, Tichauer J, Eugenín J (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112(5):1099–1114. doi: 10.1111/j.1471-4159.2009.06537.x CrossRefGoogle Scholar
  161. von Bernhardi R, Tichauer J, Eugenin-von Bernhardi L (2011) Proliferating culture of aged microglia for the study of neurodegenerative diseases. J Neurosci Methods 202(1):65–69. doi: 10.1016/j.jneumeth.2011.08.027 CrossRefGoogle Scholar
  162. von Bernhardi R, Cornejo F, Parada G, Eugenín J (2015a) Role of TGFβ signaling in the pathogenesis of Alzheimer’s disease. Front Cell Neurosci 9:426. doi: 10.3389/fncel.2015.00426 Google Scholar
  163. von Bernhardi R, Eugenin-von Bernhardi L, Eugenin J (2015b) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 7:124. doi: 10.3389/fnagi.2015.00124 Google Scholar
  164. Wang C, Tsai S, Yew T, Kwan Y, Ngai S (2010) Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8. Biogerontology 11(1):87–102. doi: 10.1007/s10522-009-9231-5 PubMedCrossRefGoogle Scholar
  165. Werry E, Enjeti S, Halliday G, Sachdev P, Double K (2010) Effect of age on proliferation-regulating factors in human adult neurogenic regions. J Neurochem 115(4):956–964. doi: 10.1111/j.1471-4159.2010.06992.x PubMedCrossRefGoogle Scholar
  166. Wu M, Hein A, Moravan M, Shaftel S, Olschowka J, O’Banion M (2012) Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running. Brain Behav Immun 26(2):292–300. doi: 10.1016/j.bbi.2011.09.012 PubMedCrossRefGoogle Scholar
  167. Wynne A, Henry C, Huang Y, Cleland A, Godbout J (2010) Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav Immun 24(7):1190–1201. doi: 10.1016/j.bbi.2010.05.011 PubMedPubMedCentralCrossRefGoogle Scholar
  168. Wyss-Coray T, Lin C, Yan F, Yu G, Rohde M, McConlogue L, Masliah E, Mucke L (2001) TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice. Nat Med 7(5):612–618. doi: 10.1038/87945 PubMedCrossRefGoogle Scholar
  169. Xiang Z, Haroutunian V, Ho L, Purohit D, Pasinetti G (2006) Microglia activation in the brain as inflammatory biomarker of Alzheimer’s disease neuropathology and clinical dementia. Dis Markers 22(1–2):95–102. doi: 10.1155/2006/276239 PubMedCrossRefGoogle Scholar
  170. Yan J, Zhang H, Yin Y, Li J, Tang Y, Purkayastha S, Li L, Cai D (2014) Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response. Nat Med 20(9):1001–1008. doi: 10.1038/nm.3616 PubMedPubMedCentralCrossRefGoogle Scholar
  171. Yankner B, Lu T, Loerch P (2008) The aging brain. Annu Rev Pathol 3:41–66. doi: 10.1146/annurev.pathmechdis.2.010506.092044 PubMedCrossRefGoogle Scholar
  172. Zhang W, Wang T, Pei Z, Miller D, Wu X, Block M, Wilson B, Zhang W, Zhou Y, Hong J-S, Zhang J (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19(6):533–542. doi: 10.1096/fj.04-2751com PubMedCrossRefGoogle Scholar
  173. Zhu Y, Carvey P, Ling Z (2006) Age-related changes in glutathione and glutathione-related enzymes in rat brain. Brain Res 1090(1):35–44. doi: 10.1016/j.brainres.2006.03.063 PubMedPubMedCentralCrossRefGoogle Scholar
  174. Zuendorf G, Kerrouche N, Herholz K, Baron J-C (2003) Efficient principal component analysis for multivariate 3D voxel-based mapping of brain functional imaging data sets as applied to FDG-PET and normal aging. Hum Brain Mapp 18(1):13–21. doi: 10.1002/hbm.10069 PubMedCrossRefGoogle Scholar
  175. Zunszain P, Anacker C, Cattaneo A, Choudhury S, Musaelyan K, Myint A, Thuret S, Price J, Pariante C (2012) Interleukin-1β: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology 37(4):939–949. doi: 10.1038/npp.2011.277 PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Departamento de Neurología, Escuela de MedicinaPontificia Universidad Católica de ChileSantiagoChile

Personalised recommendations