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Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene.

Fendrick SE, Xue QS, Streit WJ - J Neuroinflammation (2007)

Bottom Line: In animals during end stage disease at 4-5 months of age virtually all microglia in the spinal cord gray matter showed extensive fragmentation of their cytoplasm (cytorrhexis), indicative of widespread microglial degeneration.Few microglia exhibiting nuclear fragmentation (karyorrhexis) indicative of apoptosis were identified at any stage.The current findings demonstrate the occurrence of severe abnormalities in microglia, such as cell fusions and cytorrhexis, which may be the result of expression of mutant SOD1 in these cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32611, USA. sefendrick@yahoo.com

ABSTRACT

Background: Microglial neuroinflammation is thought to play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The purpose of this study was to provide a histopathological evaluation of the microglial neuroinflammatory response in a rodent model of ALS, the SOD1G93A transgenic rat.

Methods: Multiple levels of the CNS from spinal cord to cerebral cortex were studied in SOD1G93A transgenic rats during three stages of natural disease progression, including presymptomatic, early symptomatic (onset), and late symptomatic (end stage), using immuno- and lectin histochemical markers for microglia, such as OX-42, OX-6, and Griffonia simplicifolia isolectin B4.

Results: Our studies revealed abnormal aggregates of microglia forming in the spinal cord as early as the presymptomatic stage. During the symptomatic stages there was prominent formation of multinucleated giant cells through fusion of microglial cells in the spinal cord, brainstem, and red nucleus of the midbrain. Other brain regions, including substantia nigra, cranial nerve nuclei, hippocampus and cortex showed normal appearing microglia. In animals during end stage disease at 4-5 months of age virtually all microglia in the spinal cord gray matter showed extensive fragmentation of their cytoplasm (cytorrhexis), indicative of widespread microglial degeneration. Few microglia exhibiting nuclear fragmentation (karyorrhexis) indicative of apoptosis were identified at any stage.

Conclusion: The current findings demonstrate the occurrence of severe abnormalities in microglia, such as cell fusions and cytorrhexis, which may be the result of expression of mutant SOD1 in these cells. The microglial changes observed are different from those that accompany normal microglial activation, and they demonstrate that aberrant activation and degeneration of microglia is part of the pathogenesis of motor neuron disease.

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Visualization of microglia in midbrain with GSA-I-B4 lectin (A-F) and in motor cortex with OX-42 (G) and OX-6 (H) during symptomatic disease. A, low power view of midbrain reveals enhanced lectin staining in the red nucleus. B, higher magnification shows that enhanced lectin reactivity is confined strictly to red nucleus region (arrows indicate perimeter of red nucleus). C, microglial fusions are interspersed with rubrospinal neurons that appear undamaged. D, lectin-positive microglial fusion (giant cell) within red nucleus. E, oculomotor nucleus reveals normal-appearing motor neurons and lack of microgliosis. F, substantia nigra (pars compacta) shows presence of normal, ramified microglial cells. G, motor cortex shows normal, ramified microglia. H, single, ramified microglial cell positive with OX-6 (arrow) near lateral ventricle. Scale bars: 400 μm (A); 200 μm (E); 100 μm (B,H); 50 μm (C,F,G); 20 μm (D).
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Figure 5: Visualization of microglia in midbrain with GSA-I-B4 lectin (A-F) and in motor cortex with OX-42 (G) and OX-6 (H) during symptomatic disease. A, low power view of midbrain reveals enhanced lectin staining in the red nucleus. B, higher magnification shows that enhanced lectin reactivity is confined strictly to red nucleus region (arrows indicate perimeter of red nucleus). C, microglial fusions are interspersed with rubrospinal neurons that appear undamaged. D, lectin-positive microglial fusion (giant cell) within red nucleus. E, oculomotor nucleus reveals normal-appearing motor neurons and lack of microgliosis. F, substantia nigra (pars compacta) shows presence of normal, ramified microglial cells. G, motor cortex shows normal, ramified microglia. H, single, ramified microglial cell positive with OX-6 (arrow) near lateral ventricle. Scale bars: 400 μm (A); 200 μm (E); 100 μm (B,H); 50 μm (C,F,G); 20 μm (D).

Mentions: Microglial fusions similar to those seen in the spinal cord and brainstem level were found also in the red nucleus of the midbrain (Figs. 5A–D). The specificity with which these microglial fusions were restricted to the red nucleus area was remarkable, as they were visible even at the lowest magnification (Fig. 5A). Microglia outside of the red nucleus displayed normal, ramified morphology. Rubrospinal neurons appeared normal in size and morphology, as well as in number, and there was no evidence to suggest that any of these neurons were undergoing degeneration. Rubrospinal neurons were not encircled by activated microglia. It is noteworthy also that motor neurons in the oculomotor nucleus, which appears with the red nucleus in the same sections, revealed no evidence of degenerative changes, and microglia here were normal and non-activated in appearance. Similarly, microglia in the substantia nigra appeared completely normal (Fig. 5F). Somewhat surprisingly, we also found no evidence at all for microglial activation or abnormalities in the motor cortex of animals, regardless of disease stage, with any of the microglial markers employed (Figs. 5G,H).


Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene.

Fendrick SE, Xue QS, Streit WJ - J Neuroinflammation (2007)

Visualization of microglia in midbrain with GSA-I-B4 lectin (A-F) and in motor cortex with OX-42 (G) and OX-6 (H) during symptomatic disease. A, low power view of midbrain reveals enhanced lectin staining in the red nucleus. B, higher magnification shows that enhanced lectin reactivity is confined strictly to red nucleus region (arrows indicate perimeter of red nucleus). C, microglial fusions are interspersed with rubrospinal neurons that appear undamaged. D, lectin-positive microglial fusion (giant cell) within red nucleus. E, oculomotor nucleus reveals normal-appearing motor neurons and lack of microgliosis. F, substantia nigra (pars compacta) shows presence of normal, ramified microglial cells. G, motor cortex shows normal, ramified microglia. H, single, ramified microglial cell positive with OX-6 (arrow) near lateral ventricle. Scale bars: 400 μm (A); 200 μm (E); 100 μm (B,H); 50 μm (C,F,G); 20 μm (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808448&req=5

Figure 5: Visualization of microglia in midbrain with GSA-I-B4 lectin (A-F) and in motor cortex with OX-42 (G) and OX-6 (H) during symptomatic disease. A, low power view of midbrain reveals enhanced lectin staining in the red nucleus. B, higher magnification shows that enhanced lectin reactivity is confined strictly to red nucleus region (arrows indicate perimeter of red nucleus). C, microglial fusions are interspersed with rubrospinal neurons that appear undamaged. D, lectin-positive microglial fusion (giant cell) within red nucleus. E, oculomotor nucleus reveals normal-appearing motor neurons and lack of microgliosis. F, substantia nigra (pars compacta) shows presence of normal, ramified microglial cells. G, motor cortex shows normal, ramified microglia. H, single, ramified microglial cell positive with OX-6 (arrow) near lateral ventricle. Scale bars: 400 μm (A); 200 μm (E); 100 μm (B,H); 50 μm (C,F,G); 20 μm (D).
Mentions: Microglial fusions similar to those seen in the spinal cord and brainstem level were found also in the red nucleus of the midbrain (Figs. 5A–D). The specificity with which these microglial fusions were restricted to the red nucleus area was remarkable, as they were visible even at the lowest magnification (Fig. 5A). Microglia outside of the red nucleus displayed normal, ramified morphology. Rubrospinal neurons appeared normal in size and morphology, as well as in number, and there was no evidence to suggest that any of these neurons were undergoing degeneration. Rubrospinal neurons were not encircled by activated microglia. It is noteworthy also that motor neurons in the oculomotor nucleus, which appears with the red nucleus in the same sections, revealed no evidence of degenerative changes, and microglia here were normal and non-activated in appearance. Similarly, microglia in the substantia nigra appeared completely normal (Fig. 5F). Somewhat surprisingly, we also found no evidence at all for microglial activation or abnormalities in the motor cortex of animals, regardless of disease stage, with any of the microglial markers employed (Figs. 5G,H).

Bottom Line: In animals during end stage disease at 4-5 months of age virtually all microglia in the spinal cord gray matter showed extensive fragmentation of their cytoplasm (cytorrhexis), indicative of widespread microglial degeneration.Few microglia exhibiting nuclear fragmentation (karyorrhexis) indicative of apoptosis were identified at any stage.The current findings demonstrate the occurrence of severe abnormalities in microglia, such as cell fusions and cytorrhexis, which may be the result of expression of mutant SOD1 in these cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32611, USA. sefendrick@yahoo.com

ABSTRACT

Background: Microglial neuroinflammation is thought to play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The purpose of this study was to provide a histopathological evaluation of the microglial neuroinflammatory response in a rodent model of ALS, the SOD1G93A transgenic rat.

Methods: Multiple levels of the CNS from spinal cord to cerebral cortex were studied in SOD1G93A transgenic rats during three stages of natural disease progression, including presymptomatic, early symptomatic (onset), and late symptomatic (end stage), using immuno- and lectin histochemical markers for microglia, such as OX-42, OX-6, and Griffonia simplicifolia isolectin B4.

Results: Our studies revealed abnormal aggregates of microglia forming in the spinal cord as early as the presymptomatic stage. During the symptomatic stages there was prominent formation of multinucleated giant cells through fusion of microglial cells in the spinal cord, brainstem, and red nucleus of the midbrain. Other brain regions, including substantia nigra, cranial nerve nuclei, hippocampus and cortex showed normal appearing microglia. In animals during end stage disease at 4-5 months of age virtually all microglia in the spinal cord gray matter showed extensive fragmentation of their cytoplasm (cytorrhexis), indicative of widespread microglial degeneration. Few microglia exhibiting nuclear fragmentation (karyorrhexis) indicative of apoptosis were identified at any stage.

Conclusion: The current findings demonstrate the occurrence of severe abnormalities in microglia, such as cell fusions and cytorrhexis, which may be the result of expression of mutant SOD1 in these cells. The microglial changes observed are different from those that accompany normal microglial activation, and they demonstrate that aberrant activation and degeneration of microglia is part of the pathogenesis of motor neuron disease.

Show MeSH
Related in: MedlinePlus