Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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
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
Arka Subhra G, Vinay T (2010) Telomeres and inflammation: rap1 joins the ends? Cell Cycle 9. doi:10.4161/cc.9.19.13383
Balaban R, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120(4):483–495. doi:10.1016/j.cell.2005.02.001
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
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
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
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
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):1285–1291
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
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
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
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
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
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
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):46–55
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
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
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
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
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
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
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
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):17–20
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Friedrich MJ (2014) Researchers probe the aging brain in health and disease. JAMA 311(3):231–232. doi:10.1001/jama.2013.284609
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):1327–1333
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
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
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
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
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
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/sj.mp.4002055
Gravina S, Vijg J (2010) Epigenetic factors in aging and longevity. Pflugers Arch 459(2):247–258. doi:10.1007/s00424-009-0730-7
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
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
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
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):335–347
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
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
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
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
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
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):603–608
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
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
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
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
Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14(10). doi:10.1186/gb-2013-14-10-r115
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
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
Hultsch D (1998) Memory change in the aged. Cambridge University Press
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
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
Janeway C, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216. doi:10.1146/annurev.immunol.20.083001.084359
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
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
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):6309–6316
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
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
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
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
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
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
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
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
Lukiw WJ (2004) Gene expression profiling in fetal, aged, and Alzheimer hippocampus: a continuum of stress-related signaling. Neurochem Res 29(6):1287–1297
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
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
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/j.it.2004.09.015
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
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
McGeer P, McGeer E (2002) Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26(4):459–470. doi:10.1002/mus.10191
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
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):1285–1291
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
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
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
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
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
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
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
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
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
Nixon R, Mathews P, Cataldo A (2001) The neuronal endosomal-lysosomal system in Alzheimer’s disease. J Alzheimers Dis 3(1):97–107
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
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):299–320
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
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
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):718–724
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
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
Pocock J, Kettenmann H (2007) Neurotransmitter receptors on microglia. Trends Neurosci 30(10):527–535. doi:10.1016/j.tins.2007.07.007
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
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
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):29–41
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):45–59
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
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
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
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
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
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
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
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
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
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
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):161–172
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
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
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
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):1377–1386
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
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):229–234
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
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, USA
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
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
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
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
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
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
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
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
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
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):1477–1484
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
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
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
Tsurumi A, Li W (2012) Global heterochromatin loss: a unifying theory of aging? Epigenetics 7(7):680–688. doi:10.4161/epi.20540
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
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
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):138–152
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
Vaupel JW (2010) Biodemography of human ageing. Nature. doi:10.1038/nature08984
von Bernhardi R (2007) Glial cell dysregulation: a new perspective on Alzheimer disease. Neurotox Res 12(4):215–232. doi:10.1007/BF03033906
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Yankner B, Lu T, Loerch P (2008) The aging brain. Annu Rev Pathol 3:41–66. doi:10.1146/annurev.pathmechdis.2.010506.092044
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
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
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
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
Acknowledgments
This work was supported by grant FONDECYT 1131025 and fellowship CONICYT 21120013.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Cornejo, F., von Bernhardi, R. (2016). Age-Dependent Changes in the Activation and Regulation of Microglia. In: von Bernhardi, R. (eds) Glial Cells in Health and Disease of the CNS. Advances in Experimental Medicine and Biology, vol 949. Springer, Cham. https://doi.org/10.1007/978-3-319-40764-7_10
Download citation
DOI: https://doi.org/10.1007/978-3-319-40764-7_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-40762-3
Online ISBN: 978-3-319-40764-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)