Abstract
BackgroundMicroglial 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.MethodsMultiple 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.ResultsOur 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.ConclusionThe 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.
Highlights
Microglial neuroinflammation is thought to play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS)
What are the cellular targets of this toxicity? Several studies have shown that expression of mutant superoxide dismutase 1 (SOD1) limited to motor neurons is insufficient to cause motor neuron degeneration [8,9], and work by Cleveland and co-workers has generated findings, which show that toxicity to motor neurons requires damage from mutant SOD1 acting within nonneuronal cells [10] and, that microglial cells are important for late stage disease development [11]
Development of microgliosis during natural disease progression in the spinal cord The CR3 complement receptor recognized by OX-42 antibody is expressed constitutively by all resting and activated microglial cells [21]
Summary
Microglial neuroinflammation is thought to play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The discovery that SOD1 gene mutations are linked to motor neuron disease has facilitated development of transgenic rodent models to mimic human disease [1,2,5], and these have provided important leads towards understanding the molecular pathology of ALS. Several studies have shown that expression of mutant SOD1 limited to motor neurons is insufficient to cause motor neuron degeneration [8,9], and work by Cleveland and co-workers has generated findings, which show that toxicity to motor neurons requires damage from mutant SOD1 acting within nonneuronal cells [10] and, that microglial cells are important for late stage disease development [11] These findings point towards a critical involvement of microglia in motor neuron disease development, yet the nature of microglial-neuronal interactions that lead to motor neuron degeneration remains unknown. Chronic neuroinflammation is thought to be involved in the pathogenesis of ALS based on a variety of in vivo and in vitro studies concerned with studying microglial activation using both human and animal tissues [1520]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
