Figure 1.
Effect of TrkB.T1 deletion on motoneuron degeneration.
(A) Representative immunofluorescent images of lumbar spinal cord showing ChAT-positive motoneurons in 8-week-old animals. In comparison to age-matched WT controls, SOD1 transgenic mice show a small but significant loss of motoneurons. This loss was prevented by deletion of TrkB.T1 in these mice (SOD1T1−/−). (B) Histogram showing number of motor neurons at 8, 12, 16 and 20 weeks. Cell counts show a progressive decrease in number of motoneurons in SOD1 animals as compared to WT controls. The deletion of TrkB.T1 in SOD1 transgenic mice completely rescues this loss at 8 and 12 weeks. At 16 weeks this neuroprotection is partial and significant whereas at 20 weeks it is completely lost such that both the SOD1 and SOD1T1−/− groups show severe reduction in motoneuron numbers as compared to WT animals. The data are the Mean ± SEM. * indicates P<0.05. N = 6 in each group. Statistical analysis by ANOVA followed by post-hoc Tukey test.
Figure 2.
Deletion of TrkB.T1 improves the motor performance of SOD1 transgenic mice on rotarod in the early phase of the disease.
(A) Histogram showing the rotarod performance of WT, SOD1 and SOD1T1−/− animals at 8, 12, 16 and 20 weeks. At 8 weeks, both SOD1 and SOD1 T1−/− animals perform similarly to controls although SOD1 mice show some impairments. With disease progression, the SOD1 transgenic mice show a significant reduction in the amount of time spent on the rotarod at 12 and 16 weeks as compared to controls. A slight loss of motor performance is evident only at 16 weeks in the SOD1T1 −/− animals, although by 20 weeks the SOD1 and SOD1;T1−/− groups are indistinguishable. The data are the Mean ± SEM. * P<0.05. N≥7. Statistical analysis by ANOVA followed by post-hoc Tukey test. (B) Kaplan-Meier analysis of the SOD1 and SOD1T1−/− mice rotarod performance in relation to their age. Note that deletion of TrkB.T1 in the SOD1 transgenic mice delays the impairment in rotarod performance by 34 days (81.6±5.87 days, n = 10 in SOD1 versus 115.8±6.80, n = 7 in SOD1 T1−/−, p<0.05).
Figure 3.
Disease progression and survival of SOD1 and SOD1;T1−/− mice.
Histograms from Kaplan-Meier analysis showing the duration of the early phase (A) and the end stage (B) of the disease, as well as the neurological scoring (C) of SOD1 and SOD1;T1−/− mice. Deletion of TrkB.T1 delays the early phase of disease progression by 6 days (19.2±1.25 days, n = 30 in SOD1 animals versus 25.2±2.09 days n = 21 in SOD1;T1−/−, P<0.05; A). Note the similar life span between groups (B) despite the improvement in the overall neurological score at 20 wk in the SOD1;T1−/− compared to the SOD1 mutant mice (C; P<0.05).
Figure 4.
The adenosine A2A receptor agonist CGS21680 delays disease onset in SOD1 mutant mice.
CGS treatment at 12 weeks of age significantly rescues motor neuron degeneration in SOD1 mice (A; p<0.05). Analysis of rotarod data showing that treatment of SOD1 mice with CGS delays the impairment in rotarod performance by 7 days compared to untreated SOD1 mice (B; Kaplan Meier Analysis, p<0.01). CGS treatment also prolongs the duration of the early phase of the disease by 12 days (C; p<0.05) although it does not affect the mean life span of the SOD1 mutant animals (D).