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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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Lectin staining of microglia in the brainstem (level of cranial nerve VII) in wildtype animals (A) and in late symptomatic/end stage animals (B-H). Cresyl violet counterstain. A, microglia show normal ramified morphology. B, a large lectin-positive aggregate of fused microglia is evident in severely vacuolated brainstem tissue. Note enlarged perineuronal spaces to the right. C, string-like microglial fusions extend over long distances. D, breakage of neuronal process, probably a dendrite, from cell body within markedly vacuolated space (arrows). E, two multinucleated microglial giant cells are seen below a neuron with broken off process (arrow). F, large multinucleated giant cell displaying vacuolization is present amidst numerous microglial cytoplasmic fragments. G, multinucleated giant cell of the Langhans type displaying characteristic peripheral arrangement of nuclei. H, rounded lectin-positive microglial cell (arrow) within vacuolated space displays nuclear fragmentation indicative of apoptosis. Scale bars: 20 μm (A-H).
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Figure 4: Lectin staining of microglia in the brainstem (level of cranial nerve VII) in wildtype animals (A) and in late symptomatic/end stage animals (B-H). Cresyl violet counterstain. A, microglia show normal ramified morphology. B, a large lectin-positive aggregate of fused microglia is evident in severely vacuolated brainstem tissue. Note enlarged perineuronal spaces to the right. C, string-like microglial fusions extend over long distances. D, breakage of neuronal process, probably a dendrite, from cell body within markedly vacuolated space (arrows). E, two multinucleated microglial giant cells are seen below a neuron with broken off process (arrow). F, large multinucleated giant cell displaying vacuolization is present amidst numerous microglial cytoplasmic fragments. G, multinucleated giant cell of the Langhans type displaying characteristic peripheral arrangement of nuclei. H, rounded lectin-positive microglial cell (arrow) within vacuolated space displays nuclear fragmentation indicative of apoptosis. Scale bars: 20 μm (A-H).

Mentions: Sections from the brainstem at the level of cranial nerve VII during disease onset and end stage were marked by changes indicative of severe neuropathology (Fig. 4). They included prominent, widespread vacuolization of the extracellular space and hyperchromia of neuronal processes. Often neurites appeared physically separated (as if torn) from neuronal cell bodies leaving one or more distinct stumps on the perikaryon (Fig. 4D,E). The changes affecting microglia were striking in that multinucleated giant cells were present throughout any given section. These consisted of fused microglial cells that gave rise to a variety of bizarrely shaped cellular fusions which, in some cases, extended for more than one hundred micrometers in length (Figs. 4B,C,F). Microglial fusions varied in size, sometimes involving only a few cells, and other times twenty or more. Although not obviously associated with vascular channels, some microglial giant cells due to their elongated shape seemed to have formed along blood vessels (Fig. 4C). Presence of giant cells was observed in all animals regardless of whether they were at an early or late symptomatic stage of motor neuron disease. They were scattered seemingly at random throughout the brainstem and not limited to any particular nucleus or tract, and often displayed the classic morphological features of Langhans type giant cells (Fig. 4G).


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)

Lectin staining of microglia in the brainstem (level of cranial nerve VII) in wildtype animals (A) and in late symptomatic/end stage animals (B-H). Cresyl violet counterstain. A, microglia show normal ramified morphology. B, a large lectin-positive aggregate of fused microglia is evident in severely vacuolated brainstem tissue. Note enlarged perineuronal spaces to the right. C, string-like microglial fusions extend over long distances. D, breakage of neuronal process, probably a dendrite, from cell body within markedly vacuolated space (arrows). E, two multinucleated microglial giant cells are seen below a neuron with broken off process (arrow). F, large multinucleated giant cell displaying vacuolization is present amidst numerous microglial cytoplasmic fragments. G, multinucleated giant cell of the Langhans type displaying characteristic peripheral arrangement of nuclei. H, rounded lectin-positive microglial cell (arrow) within vacuolated space displays nuclear fragmentation indicative of apoptosis. Scale bars: 20 μm (A-H).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Lectin staining of microglia in the brainstem (level of cranial nerve VII) in wildtype animals (A) and in late symptomatic/end stage animals (B-H). Cresyl violet counterstain. A, microglia show normal ramified morphology. B, a large lectin-positive aggregate of fused microglia is evident in severely vacuolated brainstem tissue. Note enlarged perineuronal spaces to the right. C, string-like microglial fusions extend over long distances. D, breakage of neuronal process, probably a dendrite, from cell body within markedly vacuolated space (arrows). E, two multinucleated microglial giant cells are seen below a neuron with broken off process (arrow). F, large multinucleated giant cell displaying vacuolization is present amidst numerous microglial cytoplasmic fragments. G, multinucleated giant cell of the Langhans type displaying characteristic peripheral arrangement of nuclei. H, rounded lectin-positive microglial cell (arrow) within vacuolated space displays nuclear fragmentation indicative of apoptosis. Scale bars: 20 μm (A-H).
Mentions: Sections from the brainstem at the level of cranial nerve VII during disease onset and end stage were marked by changes indicative of severe neuropathology (Fig. 4). They included prominent, widespread vacuolization of the extracellular space and hyperchromia of neuronal processes. Often neurites appeared physically separated (as if torn) from neuronal cell bodies leaving one or more distinct stumps on the perikaryon (Fig. 4D,E). The changes affecting microglia were striking in that multinucleated giant cells were present throughout any given section. These consisted of fused microglial cells that gave rise to a variety of bizarrely shaped cellular fusions which, in some cases, extended for more than one hundred micrometers in length (Figs. 4B,C,F). Microglial fusions varied in size, sometimes involving only a few cells, and other times twenty or more. Although not obviously associated with vascular channels, some microglial giant cells due to their elongated shape seemed to have formed along blood vessels (Fig. 4C). Presence of giant cells was observed in all animals regardless of whether they were at an early or late symptomatic stage of motor neuron disease. They were scattered seemingly at random throughout the brainstem and not limited to any particular nucleus or tract, and often displayed the classic morphological features of Langhans type giant cells (Fig. 4G).

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