A series of discoveries spanning for the last few years has challenged our view of microglial function, the main form of immune defense in the brain. The surveillance of neuronal circuits executed by each microglial cell overseeing its territory occurs in the form of regular, dynamic interactions. Microglial contacts with individual neuronal compartments, such as dendritic spines and axonal terminals, ensure that redundant or dysfunctional elements are recognized and eliminated from the brain. Microglia take on a new shape that is large and amoeboid when a threat to brain integrity is detected. In this defensive form, they migrate to the endangered sites, where they help to minimize the extent of the brain insult. However, in neurodegenerative diseases that are associated with misfolding and aggregation of synaptic proteins, these vital defensive functions appear to be compromised. Many microglial functions, such as phagocytosis, might be overwhelmed during exposure to the abnormal levels of misfolded proteins in their proximity. This might prevent them from attending to their normal duties, such as the stripping of degenerating synaptic terminals, before neuronal function is irreparably impaired. In these conditions microglia become chronically activated and appear to take on new, destructive roles by direct or indirect inflammatory attack. 1. Physiological Conditions Microglial cells derive from primitive myeloid progenitors (which originate from the yolk sac) invading the central nervous system (CNS) during embryonic development. As a consequence, they are the only immune cells that permanently reside in the CNS [1–3]. In the healthy CNS, microglia occupy minimally overlapping territories in which they continuously survey their environment by structurally remodeling their ramified processes on a time scale of minutes [4–8]. These surveillant microglia can respond rapidly to any pathological stimulus resulting from injury or disease by transforming their morphology and functional behavior [9–12]. Traditionally, these changes in the microglial phenotype are referred to as microglial activation. Activated microglia have the capacity to proliferate, migrate, and release reactive oxygen species, neurotoxins, and proinflammatory and anti-inflammatory cytokines. These activated microglia can secrete trophic factors, present antigens to T cells, and phagocytose pathogens, degenerating cells, and inflammatory debris [9–11, 13–15]. In addition, they can separate presynaptic terminals from the postsynaptic neuronal parts in a process known as synaptic stripping
References
[1]
F. Ginhoux, M. Greter, M. Leboeuf et al., “Fate mapping analysis reveals that adult microglia derive from primitive macrophages,” Science, vol. 330, no. 6005, pp. 841–845, 2010.
[2]
F. Ginhoux, S. Lim, G. Hoeffel, D. Low, and T. Huber, “Origin and differentiation of microglia,” Frontiers in Cellular Neuroscience, vol. 7, article 45, 2013.
[3]
K. Kierdorf, D. Erny, T. Goldmann, V. Sander, and C. Schulz, “Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways,” Nature Neuroscience, vol. 16, pp. 273–280, 2013.
[4]
D. Davalos, J. Grutzendler, G. Yang et al., “ATP mediates rapid microglial response to local brain injury in vivo,” Nature Neuroscience, vol. 8, no. 6, pp. 752–758, 2005.
[5]
A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Neuroscience: resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science, vol. 308, no. 5726, pp. 1314–1318, 2005.
[6]
A. M. Fontainhas, M. Wang, K. J. Liang et al., “Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission,” PLoS ONE, vol. 6, no. 1, Article ID e15973, 2011.
[7]
U. B. Eyo and M. E. Dailey, “Microglia: key elements in neural development, plasticity, and pathology,” Journal of Neuroimmune Pharmacology, vol. 8, no. 3, pp. 494–509, 2013.
[8]
P. Dibaj, F. Nadrigny, H. Steffens et al., “NO mediates microglial response to acute spinal cord injury under ATP control in vivo,” Glia, vol. 58, no. 9, pp. 1133–1144, 2010.
[9]
G. W. Kreutzberg, “Microglia: a sensor for pathological events in the CNS,” Trends in Neurosciences, vol. 19, no. 8, pp. 312–318, 1996.
[10]
U.-K. Hanisch and H. Kettenmann, “Microglia: active sensor and versatile effector cells in the normal and pathologic brain,” Nature Neuroscience, vol. 10, no. 11, pp. 1387–1394, 2007.
[11]
R. M. Ransohoff and V. H. Perry, “Microglial physiology: unique stimuli, specialized responses,” Annual Review of Immunology, vol. 27, pp. 119–145, 2009.
[12]
K. Helmut, U.-K. Hanisch, M. Noda, and A. Verkhratsky, “Physiology of microglia,” Physiological Reviews, vol. 91, no. 2, pp. 461–553, 2011.
[13]
A. Bessis, C. Béchade, D. Bernard, and A. Roumier, “Microglial control of neuronal death and synaptic properties,” Glia, vol. 55, no. 3, pp. 233–238, 2007.
[14]
J. J. Neher, U. Neniskyte, and G. C. Brown, “Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration,” Frontiers in Pharmacology, vol. 3, article 27, 2012.
[15]
M. Prinz, J. Priller, S. S. Sisodia, and R. M. Ransohoff, “Heterogeneity of CNS myeloid cells and their roles in neurodegeneration,” Nature Neuroscience, vol. 14, no. 10, pp. 1227–1235, 2011.
[16]
B. D. Trapp, J. R. Wujek, G. A. Criste et al., “Evidence for synaptic stripping by cortical microglia,” Glia, vol. 55, no. 4, pp. 360–368, 2007.
[17]
K. Blinzinger and G. Kreutzberg, “Displacement of synaptic terminals from regenerating motoneurons by microglial cells,” Zeitschrift für Zellforschung und Mikroskopische Anatomie, vol. 85, no. 2, pp. 145–157, 1968.
[18]
M.-è. Tremblay, “The role of microglia at synapses in the healthy CNS: novel insights from recent imaging studies,” Neuron Glia Biology, vol. 7, pp. 67–76, 2011.
[19]
M.-è. Tremblay, B. Stevens, A. Sierra, H. Wake, A. Bessis, and A. Nimmerjahn, “The role of microglia in the healthy brain,” Journal of Neuroscience, vol. 31, no. 45, pp. 16064–16069, 2011.
[20]
S. Hellwig, A. Heinrich, and K. Biber, “The brain's best friend: microglial neurotoxicity revisited,” Frontiers in Cellular Neuroscience, 2013.
[21]
R. C. Paolicelli, G. Bolasco, F. Pagani et al., “Synaptic pruning by microglia is necessary for normal brain development,” Science, vol. 333, no. 6048, pp. 1456–1458, 2011.
[22]
C. L. Cunningham, V. Martinez-Cerdeno, and S. C. Noctor, “Microglia regulate the number of neural precursor cells in the developing cerebral cortex,” Journal of Neuroscience, vol. 33, pp. 4216–4233, 2013.
[23]
M. Hoshiko, I. Arnoux, E. Avignone, N. Yamamoto, and E. Audinat, “Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex,” Journal of Neuroscience, vol. 32, pp. 15106–15111, 2012.
[24]
O. Pascual, S. B. Achour, P. Rostaing, A. Triller, and A. Bessis, “Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 4, pp. E197–E205, 2012.
[25]
Y. Li, X. F. Du, C. S. Liu, Z. L. Wen, and J. L. Du, “Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo,” Developmental Cell, vol. 23, no. 6, pp. 1189–1202, 2012.
[26]
A. Sierra, J. M. Encinas, J. J. P. Deudero et al., “Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis,” Cell Stem Cell, vol. 7, no. 4, pp. 483–495, 2010.
[27]
C. Bechade, Y. Cantaut-Belarif, and A. Bessis, “Microglial control of neuronal activity,” Frontiers in Cellular Neuroscience, vol. 7, article 32, 2013.
[28]
D. P. Schafer, E. K. Lehrman, A. G. Kautzman, et al., “Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner,” Neuron, vol. 74, no. 4, pp. 691–705, 2012.
[29]
H. Wake, A. J. Moorhouse, S. Jinno, S. Kohsaka, and J. Nabekura, “Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals,” Journal of Neuroscience, vol. 29, no. 13, pp. 3974–3980, 2009.
[30]
M.-è. Tremblay, R. L. Lowery, and A. K. Majewska, “Microglial interactions with synapses are modulated by visual experience,” PLoS Biology, vol. 8, no. 11, Article ID e1000527, 2010.
[31]
M.-è. Tremblay, M. L. Zettel, J. R. Ison, P. D. Allen, and A. K. Majewska, “Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices,” Glia, vol. 60, no. 4, pp. 541–558, 2012.
[32]
C. J. Sogn, M. Puchades, and V. Gundersen, “Rare contacts between synapses and microglial processes containing high levels of Iba1 and actin—a postembedding immunogold study in the healthy rat brain,” European Journal of Neuroscience, vol. 32, no. 1, pp. 2030–2040, 2013.
[33]
H. Neumann, M. R. Kotter, and R. J. M. Franklin, “Debris clearance by microglia: an essential link between degeneration and regeneration,” Brain, vol. 132, no. 2, pp. 288–295, 2009.
[34]
A. Sierra, O. Abiega, A. Shahraz, and H. Neumann, “Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis,” Frontiers in Cellular Neuroscience, vol. 7, article 6, 2013.
[35]
S.-M. Lu, M.-è. Tremblay, I. L. King et al., “HIV-1 Tat-induced microgliosis and synaptic damage via interactions between peripheral and central myeloid cells,” PLoS ONE, vol. 6, no. 9, Article ID e23915, 2011.
[36]
D. F. Marker, M.-è. Tremblay, J. M. Puccini, et al., “The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders,” Journal of Neuroscience, vol. 33, no. 24, pp. 9998–10010, 2013.
[37]
T. Keck, T. D. Mrsic-Flogel, M. Vaz Afonso, U. T. Eysel, T. Bonhoeffer, and M. Hübener, “Massive restructuring of neuronal circuits during functional reorganization of adult visual cortex,” Nature Neuroscience, vol. 11, no. 10, pp. 1162–1167, 2008.
[38]
A. Majewska and M. Sur, “Motility of dendritic spines in visual cortex in vivo: changes during the critical period and effects of visual deprivation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 16024–16029, 2003.
[39]
D. Tropea, A. K. Majewska, R. Garcia, and M. Sur, “Structural dynamics of synapses in vivo correlate with functional changes during experience-dependent plasticity in visual cortex,” Journal of Neuroscience, vol. 30, no. 33, pp. 11086–11095, 2010.
[40]
M. R. Damani, L. Zhao, A. M. Fontainhas, J. Amaral, R. N. Fariss, and W. T. Wong, “Age-related alterations in the dynamic behavior of microglia,” Aging Cell, vol. 10, no. 2, pp. 263–276, 2011.
[41]
A. Sierra, A. C. Gottfried-Blackmore, B. S. Mcewen, and K. Bulloch, “Microglia derived from aging mice exhibit an altered inflammatory profile,” Glia, vol. 55, no. 4, pp. 412–424, 2007.
[42]
X.-G. Luo, J.-Q. Ding, and S.-D. Chen, “Microglia in the aging brain: relevance to neurodegeneration,” Molecular Neurodegeneration, vol. 5, no. 1, article 12, 2010.
[43]
H. Kettenmann, F. Kirchhoff, and A. Verkhratsky, “Microglia: new roles for the synaptic stripper,” Neuron, vol. 77, pp. 10–18, 2013.
[44]
W. T. Wong, “Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation,” Frontiers in Cellular Neuroscience, vol. 7, article 22, 2013.
[45]
D. J. Selkoe, “Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases,” Nature Cell Biology, vol. 6, no. 11, pp. 1054–1061, 2004.
[46]
C. Haass and D. J. Selkoe, “Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide,” Nature Reviews Molecular Cell Biology, vol. 8, no. 2, pp. 101–112, 2007.
[47]
D. M. Walsh, I. Klyubin, J. V. Fadeeva et al., “Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo,” Nature, vol. 416, no. 6880, pp. 535–539, 2002.
[48]
M. Townsend, G. M. Shankar, T. Mehta, D. M. Walsh, and D. J. Selkoe, “Effects of secreted oligomers of amyloid β-protein on hippocampal synaptic plasticity: a potent role for trimers,” Journal of Physiology, vol. 572, no. 2, pp. 477–492, 2006.
[49]
R. D. Terry, E. Masliah, D. P. Salmon et al., “Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment,” Annals of Neurology, vol. 30, no. 4, pp. 572–580, 1991.
[50]
S. W. Scheff, D. A. Price, F. A. Schmitt, and E. J. Mufson, “Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment,” Neurobiology of Aging, vol. 27, no. 10, pp. 1372–1384, 2006.
[51]
R. Malinow, “New developments on the role of NMDA receptors in Alzheimer's disease,” Current Opinion in Neurobiology, vol. 22, no. 3, pp. 559–563, 2012.
[52]
E. G. McGeer and P. L. McGeer, “Brain inflammation in Alzheimer disease and the therapeutic implications,” Current Pharmaceutical Design, vol. 5, no. 10, pp. 821–836, 1999.
[53]
M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada et al., “Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer's disease,” Nature, vol. 451, no. 7179, pp. 720–724, 2008.
[54]
A. R. Simard and S. Rivest, “Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia,” FASEB Journal, vol. 18, no. 9, pp. 998–1000, 2004.
[55]
W. Q. Qiu, Z. Ye, D. Kholodenko, P. Seubert, and D. J. Selkoe, “Degradation of amyloid β-protein by a metalloprotease secreted by microglia and other neural and non-neural cells,” Journal of Biological Chemistry, vol. 272, no. 10, pp. 6641–6646, 1997.
[56]
D. M. Paresce, R. N. Ghosh, and F. R. Maxfield, “Microglial cells internalize aggregates of the Alzheimer's disease amyloid β-protein via a scavenger receptor,” Neuron, vol. 17, no. 3, pp. 553–565, 1996.
[57]
J. El Khoury, S. E. Hickman, C. A. Thomas, L. Cao, S. C. Silverstein, and J. D. Loike, “Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils,” Nature, vol. 382, no. 6593, pp. 716–719, 1996.
[58]
J. Koenigsknecht and G. Landreth, “Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism,” Journal of Neuroscience, vol. 24, no. 44, pp. 9838–9846, 2004.
[59]
J. El Khoury, M. Toft, S. E. Hickman et al., “Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease,” Nature Medicine, vol. 13, no. 4, pp. 432–438, 2007.
[60]
J. A. Nicoll, E. Barton, D. Boche, et al., “Abeta species removal after Aβ42 immunization,” Journal of Neuropathology and Experimental Neurology, vol. 65, 11, pp. 1040–1048, 2006.
[61]
P. E. Cramer, J. R. Cirrito, D. W. Wesson et al., “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models,” Science, vol. 335, no. 6075, pp. 1503–1506, 2012.
[62]
M. T. Heneka, M. P. Kummer, A. Stutz, et al., “NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice,” Nature, vol. 493, pp. 674–678, 2013.
[63]
G. Naert and S. Rivest, “CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease,” Journal of Neuroscience, vol. 31, no. 16, pp. 6208–6220, 2011.
[64]
S. A. Grathwohl, R. E. K？lin, T. Bolmont et al., “Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia,” Nature Neuroscience, vol. 12, no. 11, pp. 1361–1363, 2009.
[65]
S. Hellwig, A. Heinrich, and K. Biber, “The brain's best friend: microglial neurotoxicity revisited,” Frontiers in Cellular Neuroscience, vol. 7, pp. 1–11, 2013.
[66]
N. H. Varvel, S. A. Grathwohl, F. Baumann, et al., “Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 44, pp. 18150–18155, 2012.
[67]
S. D. Yan, X. Chen, J. Fu et al., “RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease,” Nature, vol. 382, no. 6593, pp. 685–691, 1996.
[68]
D. T. Weldon, S. D. Rogers, J. R. Ghilardi et al., “Fibrillar β-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo,” Journal of Neuroscience, vol. 18, no. 6, pp. 2161–2173, 1998.
[69]
J. K. Harrison, Y. Jiang, S. Chen et al., “Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 18, pp. 10896–10901, 1998.
[70]
M. Fuhrmann, T. Bittner, C. K. E. Jung et al., “Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease,” Nature Neuroscience, vol. 13, no. 4, pp. 411–413, 2010.
[71]
Y. Yoshiyama, M. Higuchi, B. Zhang et al., “Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model,” Neuron, vol. 53, no. 3, pp. 337–351, 2007.
[72]
D. A. Fraser, K. Pisalyaput, and A. J. Tenner, “C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production,” Journal of Neurochemistry, vol. 112, no. 3, pp. 733–743, 2010.
[73]
S. B. Prusiner and S. J. DeArmond, “Prion diseases and neurodegeneration,” Annual Review of Neuroscience, vol. 17, pp. 311–339, 1994.
[74]
A. R. Johnston, C. Black, J. Fraser, and N. MacLeod, “Scrapie infection alters the membrane and synaptic properties of mouse hippocampal CA1 pyramidal neurones,” Journal of Physiology, vol. 500, part 1, pp. 1–15, 1997.
[75]
P. V. Belichenko, D. Brown, M. Jeffrey, and J. R. Fraser, “Dendritic and synaptic alterations of hippocampal pyramidal neurones in scrapie-infected mice,” Neuropathology and Applied Neurobiology, vol. 26, no. 2, pp. 143–149, 2000.
[76]
R. N. Hogan, J. R. Baringer, and S. B. Prusiner, “Scrapie infection diminishes spines and increases varicosities of dendrites in hamsters: a quantitative Golgi analysis,” Journal of Neuropathology and Experimental Neurology, vol. 46, no. 4, pp. 461–473, 1987.
[77]
D. M. D. Landis, R. S. Williams, and C. L. Masters, “Golgi and electron microscopic studies of spongiform encephalopathy,” Neurology, vol. 31, no. 5, pp. 538–549, 1981.
[78]
B. Caughey and G. S. Baron, “Prions and their partners in crime,” Nature, vol. 443, no. 7113, pp. 803–810, 2006.
[79]
M. Jeffrey, W. G. Halliday, J. Bell et al., “Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus,” Neuropathology and Applied Neurobiology, vol. 26, no. 1, pp. 41–54, 2000.
[80]
C. Cunningham, R. Deacon, H. Wells et al., “Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease,” European Journal of Neuroscience, vol. 17, no. 10, pp. 2147–2155, 2003.
[81]
B. C. Gray, Z. Siskova, V. H. Perry, and V. O'Connor, “Selective presynaptic degeneration in the synaptopathy associated with ME7-induced hippocampal pathology,” Neurobiology of Disease, vol. 35, no. 1, pp. 63–74, 2009.
[82]
T. Kitamoto, R.-W. Shin, K. Doh-ura et al., “Abnormal isoform of prion proteins accumulates in the synaptic structures of the central nervous system in patients with Creutzfeldt-Jakob disease,” American Journal of Pathology, vol. 140, no. 6, pp. 1285–1294, 1992.
[83]
K. Williams, E. Ulvestad, and J. Antel, “Immune regulatory and effector properties of human adult microglia studied in vitro and in situ,” Advances in Neuroimmunology, vol. 4, no. 3, pp. 273–281, 1994.
[84]
L. Manuelidis, W. Fritch, and Y.-G. Xi, “Evolution of a strain of CJD that induces BSE-like plaques,” Science, vol. 277, no. 5322, pp. 94–98, 1997.
[85]
T. A. Baker, “Protein unfolding: trapped in the act,” Nature, vol. 401, no. 6748, pp. 29–30, 1999.
[86]
D. Boche, C. Cunningham, F. Docagne, H. Scott, and V. H. Perry, “TGFβ1 regulates the inflammatory response during chronic neurodegeneration,” Neurobiology of Disease, vol. 22, no. 3, pp. 638–650, 2006.
[87]
V. A. Fadok and G. Chimini, “The phagocytosis of apoptotic cells,” Seminars in Immunology, vol. 13, no. 6, pp. 365–372, 2001.
[88]
K. Guenther, R. M. J. Deacon, V. H. Perry, and J. N. P. Rawlins, “Early behavioural changes in scrapie-affected mice and the influence of dapsone,” European Journal of Neuroscience, vol. 14, no. 2, pp. 401–409, 2001.
[89]
Z. ？i？ková, A. Page, V. O'Connor, and V. H. Perry, “Degenerating synaptic boutons in prion disease: microglia activation without synaptic stripping,” American Journal of Pathology, vol. 175, no. 4, pp. 1610–1621, 2009.
[90]
Z. Siskova, R. A. Reynolds, V. O'Connor, and V. H. Perry, “Brain region specific pre-synaptic and post-synaptic degeneration are early components of neuropathology in prion disease,” PLoS ONE, vol. 8, no. 1, Article ID e55004, 2013.
[91]
Z. Sisková, N. K. Sanyal, A. Orban, V. O'Connor, and V. H. Perry, “Reactive hypertrophy of synaptic varicosities within the hippocampus of prion-infected mice,” Biochemical Society Transactions, vol. 38, no. 2, pp. 471–475, 2010.
[92]
C. Bertoni-Freddari, P. Fattoretti, T. Casoli, W. Meier-Ruge, and J. Ulrich, “Morphological adaptive response of the synaptic junctional zones in the human dentate gyrus during aging and Alzheimer's disease,” Brain Research, vol. 517, no. 1-2, pp. 69–75, 1990.
[93]
S. T. DeKosky and S. W. Scheff, “Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity,” Annals of Neurology, vol. 27, no. 5, pp. 457–464, 1990.
[94]
L. O. Ronnevi, “Spontaneous phagocytosis of C-type synaptic terminals by spinal α-motoneurons in newborn kittens. An electron microscopic study,” Brain Research, vol. 162, no. 2, pp. 189–199, 1979.
[95]
M. Fuhrmann, G. Mitteregger, H. Kretzschmar, and J. Herms, “Dendritic pathology in prion disease starts at the synaptic spine,” Journal of Neuroscience, vol. 27, no. 23, pp. 6224–6233, 2007.
[96]
V. H. Perry and J. Teeling, “Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration,” Seminars in Immunopathology, vol. 35, no. 5, pp. 601–612, 2013.
