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Results: 8

1.
Figure 7

Figure 7. From: Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

Chromatolysis in TDP-43M337V mice. Nissl staining of motor neurons of (A) TDP-43M337V mice is much weaker than that in (B) NT mice. (C) Electron micrograph of a chromatolytic neuron of TDP-43M337V mice compared to the (D) normal neuron of the NT mouse shows rarefaction of cytoplasmic organelles (E), compared with the normal cytoplasmic density (D) and packed organelles (F) of NT mice. Scale bars: 20 μM in A and B; 5 μM in C and D; and 1 μM in E and F.

Ya-Fei Xu, et al. Mol Neurodegener. 2011;6:73-73.
2.
Figure 5

Figure 5. From: Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

Neuropathology in TDP-43M337V mice. Hematoxylin and eosin staining revealed (A, arrows) eosinophilic aggregates in spinal motor neurons from TDP-43M337V mice that are not observed in (B) NT mice. Abnormal ubiquitin immunoreactivity was present in the cytoplasm and nucleus of neurons in the (C) spinal cord of TDP-43M337V mice, but not in (D) NT mice. Similar ubiquitination was observed in the (E) cortex of TDP-43M337V mice, but not in (F) NT mice. Enhanced (G-H) GFAP and (I-J) IBA-1 immunoreactivity indicative of reactive astrogliosis and activated microglia, respectively, were observed in TDP-43M337V mice (G, I), but not NT mice (H, J). Scale bars: 100 μM.

Ya-Fei Xu, et al. Mol Neurodegener. 2011;6:73-73.
3.
Figure 8

Figure 8. From: Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

Tau pathology in TDP-43M337V mice. Immunohistochemistry of the cortices of (A) TDP-43M337V and (B) TDP-43WT mice showed elevated levels of phosphorylated tau (CP13) in both TDP-43M337V and TDP-43WT mice compared to (C) NT mice. (D) Western blotting of brain lysates from NT, TDP-43 M337V and TDP-43WT mice probed with CP13 antibody showed increases in murine tau phosphorylation at serine residues 202 in both lines of TDP-43 transgenic mice. Staining with tau-1 antibody showed reduced dephosphorylated tau levels in both lines of TDP-43 transgenic mice when compared to NT mice. Staining with antibody tau-5 showed that overall tau levels were equivalent across non-transgenic and transgenic mice. There was a dramatic increase of phospho-(Ser) PKC substrate in both TDP-43 transgenic lines indicating PKC activation that was not present in NT mice. Scale bars: 50 μM in A, B and C.

Ya-Fei Xu, et al. Mol Neurodegener. 2011;6:73-73.
4.
Figure 4

Figure 4. From: Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

Distribution of TDP-43 and phosphorylated TDP-43 (pTDP-43) aggregates in TDP-43M337V mice. Immunostaining in spinal cord sections of a 1-month old TDP-43M337V from (A) line 4, (B) line 6 and (C) NT mice shows hTDP-43 in nuclei, with occasional cytoplasmic staining (arrowhead); hTDP-43 was not observed in NT mice. (D-F) Immunostaining of spinal cord sections for total TDP-43 shows that TDP-43 immunoreactivity in both nuclei and cytoplasm in TDP-43M337V mice (arrowhead) (D-E), but only in nuclei in NT mice (F). Immunostaining of spinal cord (G-I) or cortical (J-L) neurons for phosphorylated (p403/404) TDP-43. (G-H) Nuclear bodies (arrowheads) within spinal motor neurons of TDP-43M337V mice immunostained for pTDP-43. Occasionally, diffuse cytoplasmic pTDP-43 was found within the motor neurons in the anterior horn of TDP-43M337V mice (arrows). (I) NT mice lacked similar pTDP-43 staining in the spinal cord. (J-K) Cytoplasmic aggregates of pTDP-43 (arrows) were often seen in cortical neurons of TDP-43M337V mice that were absent from (L) NT mice. Scale bars: 50 μM.

Ya-Fei Xu, et al. Mol Neurodegener. 2011;6:73-73.
5.
Figure 6

Figure 6. From: Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

Abnormal mitochondrial aggregations in TDP-43M337V mice. COX-IV immunoreactivity illustrates densely stained aggregates in a spinal motor neuron of (A) TDP-43M337V mice, but not in (B) NT mice. (C) Electron micrograph of a spinal motor neuron from a TDP-43M337V mouse shows a cluster of mitochondria surrounding a filamentous core (boxed area). (D) Enlargement of the filamentous core showing 20 nm filaments and various vesicles. Small dense granules are stain precipitates. (E) Electron micrograph of a mitochondrial aggregate in another spinal motor neuron of the TDP-43M337V mouse. Note the close proximity of mitochondria with varying degrees of degenerating inner cristae (arrowheads), compared to normal mitochondria in motor neurons of (F) NT mice. (E) The degenerating mitochondria of TDP-43M337V mice also appear smaller in size compared with those of (F) NT mice. Asterisk in (E) indicates a vacuolated mitochondrion. (F) In NT mice, mitochondria (arrows) were usually separated by other cytoplasmic organelles, e.g. rough endoplasmic reticulum (arrowheads) and ribosomes. Scale bars: 50 μM in A and B.

Ya-Fei Xu, et al. Mol Neurodegener. 2011;6:73-73.
6.
Figure 1

Figure 1. From: Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

TDP-43 expression in TDP-43 M337V mice. (A) Western blots of brain lysates from non-transgenic (NT) mice, founder line 1, 4, 6 of TDP-43M337V hemizygous mice and line 3c of TDP-43WT hemizygous mice show that TDP-43M337V (lines 4, 6) and TDP-43WT mice are expression matched for both total (mTDP-43 and hTDP-43) and hTDP-43 levels, which was subsequently confirmed (B) by densitometric measurements. Compared with NT mice (1 ± 0.04), the levels of total TDP-43 in lines 1, 4, 6 and 3c are 1.2 ± 0.05; 1.6 ± 0.07; 1.3 ± 0.17; 1.9 ± 0.22 fold respectively. Compared to line 1(1 ± 0.06), the levels of hTDP-43 of line 4, 6 and 3c are 8.3 ± 1.2; 7.7 ± 1.0 and 8.3 ± 1.3 fold, respectively. Data shown in (B) are means ± SEM of six different mice of each genotype. (C) Western blot of tissue lysates of TDP-43 M337V mice from brain (Br), spinal cord (SC), thigh muscle (TM), heart (He), stomach (St), kidney (Ki), live (Li) and spleen (Sp) probed with an antibody against hTDP-43 reveals high expression in the brain and spinal cord (line 4). (D-E) Immunohistochemistry shows hTDP-43 distributed throughout the gray matter of the spinal cord (A) and brain (B) in the hemizygous TDP-43M337V mice.

Ya-Fei Xu, et al. Mol Neurodegener. 2011;6:73-73.
7.
Figure 2

Figure 2. From: Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

Down regulation of mouse TDP-43 and production of lower molecular weight (LMW) TDP-43 species in TDP-43M337V mice. Western blots (A) of brain lysates from NT, hemizygous (Hemi) and homozygous (Homo) TDP-43M337V mice probed for hTDP-43 or total TDP-43 levels were quantified by (B) densitometry to show that mutant hTDP-43 expression is approximately 90% higher in homozygous mice compared to hemizygous mice (Hemi = 1 ± 0.04; Homo = 1.9 ± 0.06), ** p < 0.001. Densitometric analysis (C) shows that total TDP-43 levels in each genotype group (NT = 1 ± 0.05; Hemi = 1.6 ± 0.03; Homo = 2.7 ± 0.08). ** p < 0.001. Data shown are means ± SEM of six different mice of each genotype. (D) Quantitative real time PCR (qPCR) using mTDP-43-specific primers demonstrate the mRNA levels of mTDP-43 in NT, hemizygous and homozygous mice brain (NT = 1 ± 0.07; Hemi = 0.8 ± 0.05; Homo = 0.7 ± 0.01). * p < 0.05, ** p < 0.01. (E) qPCR using hTDP-43 - specific primers shows the mRNA levels of hTDP-43 in hemizygous and homozygous mice brain (Hemi = 1 ± 0.09; Homo = 1.86 ± 0.14). ** p < 0.01. Data shown in (D) and (E) are means ± SEM of four different mice of each genotype. (F) Darker exposure of the Western blot shown in (A) revealed increased LMW species of TDP-43 in hemi- and homozygous TDP-43M337V mice. (G) Densitometric analysis of ~25 kDa and ~35 kDa TDP-43 species indicates that both species correlate with total TDP-43 expression (For ~25 kDa species, NT = 1 ± 0.14; Hemi = 1.4 ± 0.21; Homo = 3.4 ± 0.26. For ~35 kDa species, NT = 1 ± 0.32; Hemi = 1.6 ± 0.28; Homo = 2.4 ± 0.13). ** p < 0.01. Data shown are means ± SEM of six different mice of each genotype.

Ya-Fei Xu, et al. Mol Neurodegener. 2011;6:73-73.
8.
Figure 3

Figure 3. From: Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

Reduced brain and body weight and motor dysfunction in TDP-43M337V mice. (A-B) Upon tail elevation, NT mice (A) showed normal escape response by splaying their hind limbs while homozygous TDP-43M337V mice (B) held their hind limbs close to their body and failed to show proper escape extension. (C-D) Gait of NT and TDP-43M337V mice was evaluated by inked foot placement on paper. 1 month old (C) NT mice show normal foot placement and gait; whereas, (D) homozygous TDP-43M337V mice showed an irregular, inwardly-placed foot falls with a dragging pattern. Forepaws and hind paws were coated in red and blue ink, respectively, to evaluate placement of paws during travel. (E) At 1 month, brain weight and (F) body weight of homozygous TDP-43M337V mice was significantly lower than that of age-matched NT and hemizygous mice. Brain weight: NT = 428 ± 9 mg; Hemi = 429 ± 11 mg; Homo = 338 ± 29 mg. Body weight: NT = 12.3 ± 1 g; Hemi = 12 ± 2 g; Homo = 6 ± 2 g. Data shown are the means ± SEM of 6-8 mice per group. ***p < 0.0001. (G) Hemizygous TDP-43M337V mice were mated, and the survival of the resulting pups of each genotype was determined. The results are plotted as a percentage of pups alive per postnatal day of life. Survival rate for all cohorts were calculated using Kaplan-Meier methods (p < 0.001 for overall log-rank test). Homozygous TDP-43M337V mice had higher mortality (about 70% death) around 1 month of age, which was statistically significant compared with NT and hemizygous littermates (p < 0.001).

Ya-Fei Xu, et al. Mol Neurodegener. 2011;6:73-73.

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