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. 2013 Feb;94(1):56-64.
doi: 10.1111/iep.12006.

Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis

Mohammad A Esmaeili  1 , Marzieh Panahi, Shilpi Yadav, Leah Hennings, Mahmoud Kiaei
Affiliations

Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis

Mohammad A Esmaeili et al. Int J Exp Pathol. 2013 Feb.

Abstract

Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Transgenic mouse lines overexpressing wild-type or mutant TDP-43 exhibit ALS-like symptom, motor abnormalities and early paralysis followed by death. Reports on lifespan and phenotypic behaviour in Prp-TDP-43 (A315T) vary, and these animals are not fully characterized. Although it has been proposed that the approximate 20% loss of motor neurons at end stage is responsible for the severe weakness and death in TDP-43 mice, this degree of neurologic damage appears insufficient to cause death. Hence we studied these mice to further characterize and determine the reason for the death. Our characterization of TDP-43 transgenic mice showed that these mice develop ALS-like symptoms that later become compounded by gastrointestinal (GI) complications that resulted in death. This is the first report of a set of pathological evidence in the GI track that is strong indicator for the cause of death of Prp-hTDP-43 (A315T) transgenic mice.

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Figures

Figure 1
Figure 1
Disease signs in TDP-43 mice. (a) Abnormal limb reflex in TDP-43 males compared to wild-type mice at different ages. (b) Disturbed footprint pattern in TDP-43 mice (at age 110 days) with markedly wide-based stance, small stride and frequent offline stumbling in transgenic mice. (c) Significant 2-fold decrease in the stride of both forelimb and hindlimb (P < 0.05). (d) Swimming gait at age 120 days and end-stage paralysis in TDP-43 male mice. TDP-43 transgenic mouse was unable to move its hindlimb or right itself when placed on its back.
Figure 2
Figure 2
Motor performance and body weight analysis. (a) TDP-43 males and non-transgenic little mate controls motor performance and body mass (n = 15 per group). (b) TDP-43 females and non-transgenic little mate control motor performance and body mass (n = 15 per group). Motor performance was assessed using a rotarod apparatus rotating at constant speed of 12 rpm and mice were scored for the length of time on the rotating rod (max 180 s), and details are described in the material and methods. Values are the mean ± SEM.
Figure 3
Figure 3
Kaplan–Meier survival curve of TDP-43 males (=15) and females (n = 10). Significant differences were determined at P < 0.0001.
Figure 4
Figure 4
(a) Symptomatic TDP-43 male near end stage appears lethargic, frozen, hunched posture (Kyphosis) and reduced mobility (arrow). (b) Photograph showing gross gastrointestinal tract with swollen intestine, enlarged caecum in TDP-43 mouse at the end stage (arrow).
Figure 5
Figure 5
Microscopic sub-gross images of Ileocecocolic transgenic mice at end stage and wild-type littermate. Ileum is markedly distended in transgenic animal (a) compared to wild type (b). Lymph node (LN) is enlarged and oedematous. Colon (c) is unaffected. Some caecal contents have been removed from affected animals to facilitate processing and sectioning. H&E stain. Bar=2 mm.
Figure 6
Figure 6
Marked diffuse vacuolization of smooth muscle fibres (arrow) in transgenic mouse (a) compared to wild type (b). H&E stain, 400× (40× objective, 10× eyepiece) magnification. Bar =50 μm.
Figure 7
Figure 7
Mucosal (lamina propria) and submucosal oedema (arrows) in the caecum (top row) and ileum (bottom row) of transgenic mouse (left column) compared to wild-type control (right column). Caecum (top row) and ileum (bottom row). 200× magnification, bar =100 μm.
Figure 8
Figure 8
Microscopic [haematoxylin and eosin (H&E) stain] images of Ileocaecal junction of transgenic mouse with serosal oedema and fibrosis. (a) H&E, 100×. (b) Trichrome, 200×. Arrows indicate collagen fibres. (c) WT control, trichrome, 200×.
Figure 9
Figure 9
Immunohistochemistry for TARDBP protein in spinal cord sections. Strong nuclear TDP-43 staining is present in the spinal cord of wild-type mice (arrows) (a); however, spinal cord neurons from TDP-43 mice (at age 110 days) stained abnormally and diffused. Some neurons have skein-like inclusions (arrow) (b).
Figure 10
Figure 10
Immunohistochemistry for TARDBP protein in intestinal sections of transgenic (a) and wild-type mice (b) at age 110 days. Vacuolation of myenteric plexus (stars) in A. Cytoplasm of ganglion cells and myocytes stains darker, with cytoplasmic aggregates (arrow) present in transgenic animal. 1000× magnification. Bar =20 μm. Insert: Negative control.
Figure 11
Figure 11
No loss of motor neurons is evident in the spinal cord of transgenic (a) compared to wild-type (b) mice at age 110 days. Immunoperoxidase stain, left: 40× magnification. Right: 400× magnification.
Figure 12
Figure 12
(a) Western blot analysis of TDP-43 level in spinal cord and intestinal (caecum) from wild-type and transgenic TDP-43 mice at end stage. Lanes 1 and 3 each contain 30 μg of total lysates from spinal cord of wild-type and transgenic mice respectively, and lanes 2 and 4 each contain 30 μg of total lysates from intestine of wild-type and transgenic mice respectively. (b) The density of TDP-43 bands is measured, and the ratios are calculated in arbitrary units.
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