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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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Schematic depicting the approximate time course of motor neuron disease development and the accompanying microglial changes in SOD1G93A rats. Note that disease onset and subsequent development of end stage disease is variable among individual animals.
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Figure 6: Schematic depicting the approximate time course of motor neuron disease development and the accompanying microglial changes in SOD1G93A rats. Note that disease onset and subsequent development of end stage disease is variable among individual animals.

Mentions: The purpose of the current study was to perform an investigation of microgliosis in a recently developed rat model of ALS involving expression of a mutated human SOD1 transgene (G93A) [5]. Although these animals, similar to their murine counterparts, reportedly mimic many of the histopathological features of human ALS, including glial activation [5,19], until now a detailed analysis of reactive microgliosis has not been performed. Our current results show that the microgliosis that occurs in SOD1G93A rats is atypical and marked by some highly unusual features in microglial cells that are indicative of cellular dysfunction. The key microglial aberrations found consist of fusion into giant cells and cytorrhexis (Fig. 6). These features are not observed normally during microglial activation and they lead us to conclude that this particular animal model of ALS is characterized by microglial degeneration rather than by microglial neuroinflammation. It is therefore conceivable that neurodegeneration occurs as a consequence of glial cell deterioration.


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)

Schematic depicting the approximate time course of motor neuron disease development and the accompanying microglial changes in SOD1G93A rats. Note that disease onset and subsequent development of end stage disease is variable among individual animals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Schematic depicting the approximate time course of motor neuron disease development and the accompanying microglial changes in SOD1G93A rats. Note that disease onset and subsequent development of end stage disease is variable among individual animals.
Mentions: The purpose of the current study was to perform an investigation of microgliosis in a recently developed rat model of ALS involving expression of a mutated human SOD1 transgene (G93A) [5]. Although these animals, similar to their murine counterparts, reportedly mimic many of the histopathological features of human ALS, including glial activation [5,19], until now a detailed analysis of reactive microgliosis has not been performed. Our current results show that the microgliosis that occurs in SOD1G93A rats is atypical and marked by some highly unusual features in microglial cells that are indicative of cellular dysfunction. The key microglial aberrations found consist of fusion into giant cells and cytorrhexis (Fig. 6). These features are not observed normally during microglial activation and they lead us to conclude that this particular animal model of ALS is characterized by microglial degeneration rather than by microglial neuroinflammation. It is therefore conceivable that neurodegeneration occurs as a consequence of glial cell deterioration.

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