3.2.2 Ultrastructural abnormality
Similar to individuals with ALS, altered ultrastructure of CNS barriers
has been reported in SOD1G93A mice (Garbuzova-Davis,
Haller, Saporta, Kolomey, Nicosia & Sanberg, 2007). Brain stem and
cervical and lumbar spinal cords of SOD1G93A mice were
assessed using electron microscopy, and degenerating endothelial cells,
vacuolated endothelial cytoplasm, and swollen astrocyte end-feet were
noted at an early disease stage that worsened with disease progression.
A thickened basement membrane was noted around the severely degenerated
endothelia of all three regions assessed, suggesting a reparative
process (Garbuzova-Davis, Haller, Saporta, Kolomey, Nicosia & Sanberg,
2007). In their subsequent study, reduced laminin-1 (major
non-collagenous basement membrane glycoprotein) was demonstrated
immunohistochemically in the BSCB of SOD1G93A mice at
both early and late stages (Garbuzova-Davis et al., 2007). In line with
this, reduced and undetectable collagen IV content was reported in the
BSCB basement membrane of SOD1G93A mice (Miyazaki et
al., 2011). These ALS-related modifications at the BSCB were also
identified in SOD1G93A rats (Nicaise et al., 2009).
Despite progression of ALS pathology being more rapid in the
SOD1G93A rat model, ultrastructural alterations were
only observed in symptomatic SOD1G93A rats but not
pre-symptomatic rats. Overall, these studies suggest a compromised BSCB
structural integrity in SOD1G93A models, and that this
may lead to increased penetration of drugs into the spinal cord,
however, functional studies to confirm this hypothesis are lacking.
Furthermore, little information is available on any potential
ultrastructural changes at the BBB of the motor cortex in
SOD1G93A mice, an area which is important to
investigate to appreciate the impact of the disease on brain access of
drugs.