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. 2015 Jan 15;2(2):167–184. doi: 10.1002/acn3.162

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© 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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AAV-mediated silencing of human SOD1 in motoneurons and/or astrocytes rescues neuromuscular function and increases lifespan of ^G93^ASOD1 mice. (A) Following ICV injection of newborn mice, AAV6 coupled with the cmv promoter preferentially leads to GFP expression in NeuN-positive motoneurons, whereas AAV9-gfaABC₁D specifically targets astrocytes. Represented are hemisections of lumbar spinal cords immunolabeled for GFP and either NeuN or GFAP. Scale bar: 250 μm. (B) Quantification of the percentage of GFP-positive cells colabeling with either NeuN, VAChT, GFAP, Iba1 or Olig-2 following ICV injection of AAV6-cmv:GFP or AAV9-gfaABC₁D:GFP. Animals per group: n = 4. (C) Representation of the absolute number of GFP-positive astrocytes found per spinal cord section following ICV injection of AAV6-cmv:GFP or AAV9-gfaABC₁D:GFP. (D) Compound muscular action potential (CMAP) values representing neuromuscular function were recorded from triceps surae of treated and control animals. Neuromuscular function appears to be maintained in AAV-injected animals compared to transgenic controls. AAV6:miR SOD1: n = 10, AAV9:miR SOD1: n = 9, AAV6 + AAV9:miR SOD1: n = 11, transgenic PBS: n = 13, WT PBS: n = 15. Note that CMAP values are significantly decreased at days 60, 75, and 90 in the AAV9:miR SOD1 group with respect to WT PBS (P < 0.001). (E) Swimming performance over disease course reveals improved motor abilities in treated animals. AAV6:miR SOD1: n = 8, AAV9:miR SOD1: n = 9, AAV6 + AAV9:miR SOD1: n = 10, transgenic PBS: n = 13, WT PBS: n = 15. (F) Kaplan–Meier representing disease onset, as defined by the day when mice reach their peak body weight. AAV6:miR SOD1 significantly delays median disease onset by 30 days when compared to PBS-injected ^G93^ASOD1 mice (transgenic PBS: 120 ± 5.6, AAV6:miR SOD1: 150 ± 21.5, AAV9:miR SOD1: 120 ± 7.5, AAV6 + AAV9:miR SOD1: 135 ± 17.6). (G) Kaplan–Meier representing entry into end disease stage, as defined by the time when mice show 10% weight loss from their peak body weight. AAV9:miR SOD1 significantly prolongs early disease phase by 34 days when compared to control animals. (H) Kaplan–Meier survival curve of AAV-injected and control animals. AAV6:miR SOD1: n = 10, AAV9:miR SOD1: n = 9, AAV6 + AAV9:miR SOD1: n = 11, transgenic PBS: n = 13, WT PBS: n = 15. Values are expressed as mean ± standard deviation. One-way ANOVA and Newman–Keuls post hoc test. Two-way ANOVA and Newman–Keuls post hoc test was used for evaluation of the significance of group effect on CMAP values and swimming performance. ***P < 0.001. SOD1, superoxide dismutase 1; ICV, intracerebroventricular; WT, wild-type.