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Life and Death of Microglia

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Abstract

The importance of microglial cells in the maintenance of a well-functioning central nervous system (CNS) cannot be overstated. As descendants of the myelomonocytic lineage they are industrious housekeepers and watchful sentries that safeguard a homeostatic environment through a number of mechanisms designed to provide protection of fastidious neurons at all times. Microglia become particularly active after homeostasis has been perturbed by physical injury or other insults and they enter into a state of activation which is determined largely by the nature and severity of the lesion. Microglial activation is the main cellular event in acute neuroinflammation and essential for wound healing in the CNS. Recent studies from this laboratory have been focused on microglia in the aging brain and identified structural abnormalities, termed microglial dystrophy, that are consistent with cell senescence and progress to a form of accidental cell death that is marked by cytoplasmic degeneration and has been termed cytorrhexis. Cytorrhexis of microglia is infrequent in the normally aged human brain and non-detectable in aged rodents, but its occurrence increases dramatically during neurodegenerative conditions, including Alzheimer’s disease (AD) in humans and motoneuron disease in transgenic rats. The identification of degenerating microglia has given rise to a novel theory of AD pathogenesis, the microglial dysfunction hypothesis, which views the loss of microglial neuroprotection as a central event in neurodegenerative disease development.

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References

  • Akiyama H, McGeer PL (1990) Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 30:81–93

    Article  PubMed  Google Scholar 

  • Alliot F, Godin I, Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117:145–152

    Article  PubMed  Google Scholar 

  • Alliot F, Lecain E, Grima B, Pessac B (1991) Microglial progenitors with a high proliferative potential in the embryonic and adult mouse brain. Proc Natl Acad Sci U S A 88:1541–1545

    Article  PubMed  Google Scholar 

  • Berbel P, Innocenti GM (1988) The development of the corpus callosum in cats: a light- and electron-microscopic study. J Comp Neurol 276:132–156

    Article  PubMed  Google Scholar 

  • Bessis A, Bechade C, Bernard D, Roumier A (2007) Microglial control of neuronal death and synaptic properties. Glia 55:233–238

    Article  PubMed  Google Scholar 

  • Blinzinger K, Kreutzberg G (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial celss. Zeitschrift fur Zellforschung 85:145–157

    Article  Google Scholar 

  • Brockhaus J, Moller T, Kettenmann H (1996) Phagocytozing ameboid microglial cells studied in a mouse corpus callosum slice preparation. Glia 16:81–90

    Article  PubMed  Google Scholar 

  • Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia: new concepts. Brain Res Rev 53:344–354

    Article  PubMed  Google Scholar 

  • Cho BP, Song DY, Sugama S, Shin DH, Shimizu Y, Kim SS et al (2006) Pathological dynamics of activated microglia following medial forebrain bundle transection. Glia 53:92–102

    Article  PubMed  Google Scholar 

  • Conde JR, Streit WJ (2006a) Effect of aging on the microglial response to peripheral nerve injury. Neurobiol Aging 27:1451–1461

    Article  PubMed  Google Scholar 

  • Conde JR, Streit WJ (2006b) Microglia in the aging brain. J Neuropathol Exp Neurol 65:199–203

    PubMed  Google Scholar 

  • Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB (2005) Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflammation 2:14

    Article  PubMed  Google Scholar 

  • Cuadros MA, Navascues J (1998) The origin and differentiation of microglial cells during development. Prog Neurobiol 56:173–189

    Article  PubMed  Google Scholar 

  • Cuadros MA, Garcia-Martin M, Martin C, Rios A (1991) Haemopoietic phagocytes in the early differentiating avian retina. J Anat 177:145–158

    PubMed  Google Scholar 

  • Cullheim S, Thams S (2007) The microglial networks of the brain and their role in neuronal network plasticity after lesion. Brain Res Rev 55:89–96

    Article  PubMed  Google Scholar 

  • Dickson DW, Crystal HA, Mattiace LA, Masur DM, Blau AD, Davies P et al (1992) Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 13:179–189

    Article  PubMed  Google Scholar 

  • Dihne M, Block F, Korr H, Topper R (2001) Time course of glial proliferation and glial apoptosis following excitotoxic CNS injury. Brain Res 902:178–189

    Article  PubMed  Google Scholar 

  • Dijkstra CD, Dopp EA, Joling P, Kraal G (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54:589–599

    PubMed  Google Scholar 

  • Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16:2508–2521

    PubMed  Google Scholar 

  • Fendrick SE, Xue QS, Streit WJ (2007) Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene. J Neuroinflammation 4:9

    Article  PubMed  Google Scholar 

  • Fishman PS, Savitt JM (1989) Selective localization by neuroglia of immunoglobulin G in normal mice. J Neuropathol Exp Neurol 48:212–220

    Article  PubMed  Google Scholar 

  • Flanary BE, Streit WJ (2004) Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45:75–88

    Article  PubMed  Google Scholar 

  • Gehrmann J, Banati RB (1995) Microglial turnover in the injured CNS: activated microglia undergo delayed DNA fragmentation following peripheral nerve injury. J Neuropathol Exp Neurol 54:680–688

    Article  PubMed  Google Scholar 

  • Giulian D, Ingeman JE (1988) Colony-stimulating factors as promoters of ameboid microglia. J Neurosci 8:4707–4717

    PubMed  Google Scholar 

  • Graeber MB, Streit WJ (1990a) Microglia: immune network in the CNS. Brain Pathol 1:2–5

    Article  PubMed  Google Scholar 

  • Graeber MB, Streit WJ (1990b) Perivascular microglia defined. Trends Neurosci 13:366

    Article  PubMed  Google Scholar 

  • Graeber MB, Streit WJ, Kreutzberg GW (1988) Axotomy of the rat facial nerve leads to increased CR3 complement receptor expression by activated microglial cells. J Neurosci Res 21:18–24

    Article  PubMed  Google Scholar 

  • Graeber MB, Lopez-Redondo F, Ikoma E, Ishikawa M, Imai Y, Nakajima K et al (1998) The microglia/macrophage response in the neonatal rat facial nucleus following axotomy. Brain Res 813:241–253

    Article  PubMed  Google Scholar 

  • Hailer NP, Heppner FL, Haas D, Nitsch R (1997) Fluorescent dye prelabelled microglial cells migrate into organotypic hippocampal slice cultures and ramify. Eur J Neurosci 9:863–866

    Article  PubMed  Google Scholar 

  • Hayes GM, Woodroofe MN, Cuzner ML (1987) Microglia are the major cell type expressing MHC class II in human white matter. J Neurol Sci 80:25–37

    Article  PubMed  Google Scholar 

  • Heppner FL, Skutella T, Hailer NP, Haas D, Nitsch R (1998) Activated microglial cells migrate towards sites of excitotoxic neuronal injury inside organotypic hippocampal slice cultures. Eur J Neurosci 10:3284–3290

    Article  PubMed  Google Scholar 

  • Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 28:8354–8360

    Article  PubMed  Google Scholar 

  • Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A et al (2008) Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223

    Article  PubMed  Google Scholar 

  • Hurley SD, Walter SA, Semple-Rowland SL, Streit WJ (1999) Cytokine transcripts expressed by microglia in vitro are not expressed by ameboid microglia of the developing rat central nervous system. Glia 25:304–309

    Article  PubMed  Google Scholar 

  • Jones LL, Banati RB, Graeber MB, Bonfanti L, Raivich G, Kreutzberg GW (1997) Population control of microglia: does apoptosis play a role? J Neurocytol 26:755–770

    Article  PubMed  Google Scholar 

  • Kaur C, You Y (2000) Ultrastructure and function of the amoeboid microglial cells in the periventricular white matter in postnatal rat brain following a hypoxic exposure. Neurosci Lett 290:17–20

    Article  PubMed  Google Scholar 

  • Kaur C, Dheen ST, Ling EA (2007) From blood to brain: amoeboid microglial cell, a nascent macrophage and its functions in developing brain. Acta Pharmacol Sin 28:1087–1096

    Article  PubMed  Google Scholar 

  • Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    Article  PubMed  Google Scholar 

  • Kullberg S, Aldskogius H, Ulfhake B (2001) Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord. Brain Res 899:169–186

    Article  PubMed  Google Scholar 

  • Lambertsen KL, Clausen BH, Babcock AA, Gregersen R, Fenger C, Nielsen HH et al (2009) Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci 29:1319–1330

    Article  PubMed  Google Scholar 

  • Ling EA, Wong WC (1993) The origin and nature of ramified and amoeboid microglia: a historical review and current concepts. Glia 7:9–18

    Article  PubMed  Google Scholar 

  • Lopes KO, Sparks DL, Streit WJ (2008) Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia 56:1048–1060

    Article  PubMed  Google Scholar 

  • Lopez-Redondo F, Nakajima K, Honda S, Kohsaka S (2000) Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy. Brain Res Mol Brain Res 76:429–435

    Article  PubMed  Google Scholar 

  • Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, Craft S et al (2008) Cognitive function over time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol 65:896–905

    Article  PubMed  Google Scholar 

  • Milligan CE, Cunningham TJ, Levitt P (1991a) Differential immunochemical markers reveal the normal distribution of brain macrophages and microglia in the developing rat brain. J Comp Neurol 314:125–135

    Article  PubMed  Google Scholar 

  • Milligan CE, Levitt P, Cunningham TJ (1991b) Brain macrophages and microglia respond differently to lesions of the developing and adult visual system. J Comp Neurol 314:136–146

    Article  PubMed  Google Scholar 

  • Moller T, Hanisch UK, Ransom BR (2000) Thrombin-induced activation of cultured rodent microglia. J Neurochem 75:1539–1547

    Article  PubMed  Google Scholar 

  • Monier A, Adle-Biassette H, Delezoide AL, Evrard P, Gressens P, Verney C (2007) Entry and distribution of microglial cells in human embryonic and fetal cerebral cortex. J Neuropathol Exp Neurol 66:372–382

    Article  PubMed  Google Scholar 

  • Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132:288–295

    Article  PubMed  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    Article  PubMed  Google Scholar 

  • Ogura K, Ogawa M, Yoshida M (1994) Effects of ageing on microglia in the normal rat brain: immunohistochemical observations. Neuroreport 5:1224–1226

    PubMed  Google Scholar 

  • Perry VH, Matyszak MK, Fearn S (1993) Altered antigen expression of microglia in the aged rodent CNS. Glia 7:60–67

    Article  PubMed  Google Scholar 

  • Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9:259–270

    Article  PubMed  Google Scholar 

  • Rabchevsky AG, Degos JD, Dreyfus PA (1999) Peripheral injections of Freund's adjuvant in mice provoke leakage of serum proteins through the blood-brain barrier without inducing reactive gliosis. Brain Res 832:84–96

    Article  PubMed  Google Scholar 

  • Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145

    Article  PubMed  Google Scholar 

  • Schwartz M, Butovsky O, Bruck W, Hanisch UK (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74

    Article  PubMed  Google Scholar 

  • Sheffield LG, Berman NE (1998) Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging 19:47–55

    Article  PubMed  Google Scholar 

  • Sorokin SP, Hoyt RF Jr, Blunt DG, McNelly NA (1992) Macrophage development: II. Early ontogeny of macrophage populations in brain, liver, and lungs of rat embryos as revealed by a lectin marker. Anat Rec 232:527–550

    Article  PubMed  Google Scholar 

  • Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33:256–266

    Article  PubMed  Google Scholar 

  • Stolzing A, Grune T (2003) Impairment of protein homeostasis and decline of proteasome activity in microglial cells from adult Wistar rats. J Neurosci Res 71:264–271

    Article  PubMed  Google Scholar 

  • Streit WJ (2001) Microglia and macrophages in the developing CNS. Neurotoxicology 22:619–624

    Article  PubMed  Google Scholar 

  • Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139

    Article  PubMed  Google Scholar 

  • Streit WJ (2004) Microglia and Alzheimer's disease pathogenesis. J Neurosci Res 77:1–8

    Article  PubMed  Google Scholar 

  • Streit WJ (2005) Microglia and neuroprotection: implications for Alzheimer's disease. Brain Res Brain Res Rev 48:234–239

    Article  PubMed  Google Scholar 

  • Streit WJ (2006) Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci 29:506–510

    Article  PubMed  Google Scholar 

  • Streit WJ, Sparks DL (1997) Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med 75:130–138

    Article  PubMed  Google Scholar 

  • Streit WJ, Graeber MB, Kreutzberg GW (1989) Expression of Ia antigen on perivascular and microglial cells after sublethal and lethal motor neuron injury. Exp Neurol 105:115–126

    Article  PubMed  Google Scholar 

  • Streit WJ, Semple-Rowland SL, Hurley SD, Miller RC, Popovich PG, Stokes BT (1998) Cytokine mRNA profiles in contused spinal cord and axotomized facial nucleus suggest a beneficial role for inflammation and gliosis. Exp Neurol 152:74–87

    Article  PubMed  Google Scholar 

  • Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45:208–212

    Article  PubMed  Google Scholar 

  • Streit WJ, Miller KR, Lopes KO, Njie E (2008) Microglial degeneration in the aging brain—bad news for neurons? Front Biosci 13:3423–3438

    Article  PubMed  Google Scholar 

  • Streit WJ, Braak H, Xue QS, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. doi:10.1007/s00401-009-0556-6

  • Takahashi K, Yamamura F, Naito M (1989) Differentiation, maturation, and proliferation of macrophages in the mouse yolk sac: a light-microscopic, enzyme-cytochemical, immunohistochemical, and ultrastructural study. J Leukoc Biol 45:87–96

    PubMed  Google Scholar 

  • Theele DP, Streit WJ (1993) A chronicle of microglial ontogeny. Glia 7:5–8

    Article  PubMed  Google Scholar 

  • Thored P, Heldmann U, Gomes-Leal W, Gisler R, Darsalia V, Taneera J et al (2009) Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia 57(8):835–849

    Article  PubMed  Google Scholar 

  • Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980

    Article  PubMed  Google Scholar 

  • Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall GP 2nd et al (2006) Microglia instruct subventricular zone neurogenesis. Glia 54:815–825

    Article  PubMed  Google Scholar 

  • Wilson S, Raghupathi R, Saatman KE, MacKinnon MA, McIntosh TK, Graham DI (2004) Continued in situ DNA fragmentation of microglia/macrophages in white matter weeks and months after traumatic brain injury. J Neurotrauma 21:239–250

    Article  PubMed  Google Scholar 

  • Xue QS, Sparks DL, Streit WJ (2007) Microglial activation in the hippocampus of hypercholesterolemic rabbits occurs independent of increased amyloid production. J Neuroinflammation 4:20

    Article  PubMed  Google Scholar 

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Correspondence to Wolfgang J. Streit.

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Supported by: National Institutes of Health Grant AG023665.

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Streit, W.J., Xue, QS. Life and Death of Microglia. J Neuroimmune Pharmacol 4, 371–379 (2009). https://doi.org/10.1007/s11481-009-9163-5

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  • DOI: https://doi.org/10.1007/s11481-009-9163-5

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