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Science 330 (6005): 783-788

Copyright © 2010 by the American Association for the Advancement of Science

Changing Face of Microglia

Manuel B. Graeber

Brain and Mind Research Institute, University of Sydney, Camperdown, NSW 2050, Australia. E-mail: manuel{at}graeber.net


Figure 1
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Fig. 1. Schematic drawing showing the microglial activation cascade and associated phenotypic plasticity [modified from (7)]. (A) Ramified "resting" microglia (arrows) in the normal rat facial nucleus labeled with the use of the OX-42 monoclonal antibody, which recognizes the rat equivalent of human CD11b, the iC3b complement receptor. (B) Activated microglia (arrows), still ramified but with stouter cell processes 24 hours after facial nerve axotomy. (C) OX-42 immunoreactive perineuronal microglial cell (large arrow) and microglial processes (small arrows) apposed to a regenerating facial motor neuron (n) 4 days post axotomy [(A to C) taken from figures 1 and 2 of Graeber et al. (4)]. (D) Image from day 4 after facial nerve axotomy, a microglial cell process (m) on the surface of a regenerating facial motoneuron (n). Two short pseudopods (p) can be seen arising from the microglial cell process embracing a displaced axonal terminal [a, yellow; from figure 5 of Blinzinger and Kreutzberg (28)]. (E) Macrophages can develop from activated microglia, but this transformation is tightly controlled in vivo; that is, there is a substantial threshold that needs to be overcome [symbolized in (F)]. OX-42 labeling of phagocytic facial nucleus microglia (larger arrows) [taken from figure 2 of Graeber et al. (53)]. Scale bar: 50 µm in (A), (B), and (E); 30 µm in (C); 2 µm in (D).

 

Figure 2
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Fig. 2. [11C](R)-PK11195 positron emission tomography images of a patient with predominantly left-hemispheric fronto-temporal lobar dementia (age, 69 years; disease duration, 3 years) (B, E, H) coregistered to the same patient’s magnetic resonance imaging scans (A, D, G). The red in the volume-render magnetic resonance imaging scans (C, F, I) indicates areas of substantial atrophy. These areas overlap with the regional pattern of increased [11C](R)-PK11195 signal. At the bottom of the image, the color bar denotes [11C](R)-PK11195 binding potential values between 0 and 1. The images are shown in radiological convention; that is, the left side of the image is the right of the patient, indicated by R. (F) Top-down view onto the cortex with the right side of the image also being the right of the patient. (G and H) Sagittal sections through the left hemisphere. [Courtesy of R. B. Banati, Sydney (54)]

 

Figure 3
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Fig. 3. Microglial rod cells expressing MHC class II molecules in a case of SSPE (A) and rod cells (B), as depicted by Spielmeyer (55). The arrow in (A) points to a single rod cell. "n" denotes a pyramidal neuron that is tightly wrapped by microglial cell processes; "III" and "V" indicate cortical layers. Human cerebral cortex is labeled with the use of the CR3/43 monoclonal antibody that recognizes the beta-chain of HLA-DR, DQ, and DP. Microglial rod cells arguably represent the most intriguing microglial phenotype, because they are typically found in the cerebral cortex in association with cognitive symptoms; they show a great affinity for neuronal surfaces and, notably, dendrites; they are not normally phagocytic; they adjust their shape to an extreme extent; and they represent the longest known but least investigated microglial phenotype. Scale bar: 60 µm.

 

Figure 4
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Fig. 4. (A) MHC class II immunoreactive "sick" microglial cell severely affected by spongiform change in Creutzfeldt-Jakob disease. The arrows point to large vacuoles that have destroyed the normal structure of the microglial cell processes. Scale bar: 10 µm. [Reproduced with permission from the Journal of Neuropathology and Experimental Neurology (56)] (B) Rio-Hortega’s drawing of a microglial cell (57). There are no vacuoles in normal state [compare with (A)], nor is there any fragmentation of cell processes [compare with (C)]. (C) Microglial fragmentation precedes the spread of tau pathology in the temporal lobe of Alzheimer’s patients. Double-label immunohistochemistry for microglia (iba1) and tau (AT8) is shown in three subjects with tau pathology increasing from Braak stage 0 to stage III. Camera lucida drawings of the actual sections are shown in (c), (f), and (i), indicating the uncus for orientation purposes, as well as both sampling areas in the entorhinal cortex (EC) and the middle temporal gyrus (MTG); areas of tau pathology are shaded orange. Representative micrographs of the EC (a, d, g) and MTG (b, e, h) reveal microglia (brown) and tau pathology (black) at the different stages. Normal ramified microglia are evident at stage 0 in both EC and MTG in the absence of tau pathology (a, b). Mostly fragmented microglia are seen in association with a neurofibrillary tangle and neuropil threads in (d), whereas mostly ramified and only a single fragmented cell (arrow) are present in (e) during stage I. Severe microglial fragmentation and loss of discernable cell shape are colocalized with extensive tau pathology in (g); microglial processes are fragmented also in (h) in the absence of neurodegeneration, but cells retain recognizable contours. Scale bar: 50 µm (a, b, d, e, g, h). [Reproduced from (40) with permission]

 


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