Magnetic Resonance Microscopy and Immunohistochemistry of the CNS of the Mutant SOD Murine Model of ALS Reveals Widespread Neural Deficits

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons and descending motor tracts of the CNS. We have evaluated the CNS of a murine model of familial ALS based on the over-expression of mutant human superoxide dismutase (mSOD; G93A) using magnetic resonance microscopy (MRM) and immunohistochemistry (IHC). Three-dimensional volumetric analysis was performed from 3D T2*-weighted images acquired at 17.6 T at isotropic resolutions of 40 mum. Compared to controls, mSOD mice had significant reductions in the volumes of total brain, substantia nigra, striatum, hippocampus, and internal capsule, with decreased cortical thickness in primary motor and somatosensory cortices. In the spinal cord, mSOD mice had significantly decreased volume of both the total grey and white matter; in the latter case, the volume change was confined to the dorsal white matter. Increased apoptosis, GFAP positive astrocytes, and/or activated microglia were observed in all those CNS regions that showed volume loss except for the hippocampus. The MRM findings in mSOD over-expressing mice are similar to data previously obtained from a model of ALS-parkinsonism dementia complex (ALS-PDC), in which neural damage occurred following a diet of washed cycad flour containing various neurotoxins. The primary difference between the two models involves a significantly greater decrease in spinal cord white matter volume in mSOD mice, perhaps reflecting variations in degeneration of the descending motor tracts. The extent to which several CNS structures are impacted in both murine models of ALS argues for a reevaluation of the nature of the pathogenesis of ALS since CNS structures involved in Parkinson's and Alzheimer's diseases appear to be affected as well.

Gene, Cell, and Axon Changes in the Familial Amyotrophic Lateral Sclerosis Mouse Sensorimotor Cortex

“…Interestingly, we observed mild activation of astrocytes in the motor cortex of presymptomatic Tg mice, which was then marked in the terminal stage of disease, when also microglia were highly activated at the same sites. In the motor cortex of SOD1(G93A) mice, increase in the number of microglial cells and a trend toward an increase of astrocytes were previously mentioned at the end stage (8), but no glial cell changes were detected in the cortex in another study (12). The present qualitative and quantitative approach has revealed selective activation of astrocytes and microglia intermingled with corticospinal neurons.…”

“…Reduction of cortical thickness detected by neuroimaging (8) and progressive loss of corticospinal and bulbospinal neurons retrogradely labeled after tracer injection at low thoracic spinal level have also been reported in these mice (9). Loss of neurons retrogradely labeled from the lower spinal cord could, however, reflect loss of axon terminals taking up the tracer at these levels with the parent corticospinal cell bodies preserved by the axon collaterals they distribute at more rostral segments (10,11).…”

“…The recent histopathological survey did not detect inflammatory changes in the cerebral cortex of SOD1(G93A) mice despite evidence of marked inflammatory pathology at subcortical levels (12); by contrast, activation of glial cells in the cortex of these mice was mentioned in another study (8). Particularly in view of the key role ascribed to glia in the disease pathogenesis, therefore, this issue requires further detailed investigation.…”

Magnetic resonance microimaging of the spinal cord in the SOD1 mouse model of amyotrophic lateral sclerosis detects motor nerve root degeneration

“…Numerous studies have also assessed white matter integrity in mouse models of spinal cord injury, using diffusion tensor imaging Kim et al, 2010;Loy et al, 2007;Tu et al, 2010), T1-and T2-weighted imaging (Gonzalez-Lara et al, 2009;Levene et al, 2008;Nishi et al, 2007), and MRM (Bilgen, 2007). In mouse models of ALS, MRM has been used to show a decrease in total white matter volume of the spinal cord (Petrik et al, 2007) …”

The Neuroinflammation in the Physiopathology of Amyotrophic Lateral Sclerosis

“…Microgliosis occurs in pre-symptomatic and symptomatic SOD1 G93A spinal cords as well as within various CNS compartments [90][91][92][93]. Similarly, SOD1 G37R mice display microgliosis at both onset and early-stage of the disease [94].…”