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AD-related Research Models
Phenotypes Examined
- Plaques
- Tangles
- Neuronal Loss
- Gliosis
- Synaptic Loss
- Changes in LTP/LTD
- Cognitive Impairment
When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.
hTDP-43ΔNLS
Observed
-
Motor Impairment at 1
Spastic motor impairment indicated by an abnormal clasping response as early as one week after transgene induction. A variety of motor deficits develop by one month after transgene induction, including impaired coordination on the Rotarod and decreased grip strength.
-
Cortical Neuron Loss at 4
Severe neuronal degeneration in the dentate gyrus and deep layers of the neocortex. Other regions, such as the hippocampal CA1 subfield and olfactory bulb, were relatively resistant to neurodegeneration. Approximately 50 percent of dentate gyrus neurons were lost one month after the transgene was activated.
-
Gliosis at 4
Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.
Absent
-
Lower Motor Neuron Loss at
Not observed.
-
Cytoplasmic Inclusions at
High levels of cytosolic TDP-43 but only very rare aggregates (observed in less than 1 percent of cortical neurons and even rarer in other brain regions, such as the hippocampus and striatum).
-
Muscle Atrophy at
Not observed.
-
Premature Death at
Not observed.
No Data
-
NMJ Abnormalities at
Unknown.
-
Body Weight at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Severe neuronal loss and gliosis in the dentate gyrus and deep cortical layers. Only very rare cytoplasmic aggregates of TDP-43 despite high levels of cytosolic protein. Degeneration of the corticospinal tract, but no lower motor neuron loss or muscle atrophy. |
A variety of motor, cognitive, and social deficits, including abnormal clasping response, impaired coordination on the Rotarod, decreased grip strength, impaired recognition and spatial memory, and decreased social behavior. Cognitive and motor impairments largely reversible in young mice following short-term transgene suppression. |
NEFH-tTA x hTDP-43ΔNLS
Observed
-
Motor Impairment at 0
rNLS8 mice develop a variety of motor impairments, starting with a deficit in hindlimb clasping and a fine tremor in the forelimb and/or hindlimb. They also develop progressive loss of grip strength (as measured by the wire-hang test) and a progressive decline in coordinated movement and balance (as measured by the accelerating Rotarod).
-
Cortical Neuron Loss at 0
Decreased cortical thickness indicative of neuronal degeneration beginning at four weeks off dox. By end stage, rNLS8 mice had significantly smaller brains than non-Tg littermates.
-
Lower Motor Neuron Loss at 0
rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.
-
Cytoplasmic Inclusions at 0
Cytoplasmic inclusions of TDP-43 occur as early as one week off dox in neurons in the brain. Inclusions accumulate over time and are present in many brain regions, including the motor cortex. TDP-43 inclusions are relatively rare in the spinal cord. Ubiquitin-positive inclusions are also seen.
-
NMJ Abnormalities at 0
Denervation of the hindlimb muscle tibialis anterior was detectable by four weeks off dox, that is, two weeks prior to detectable loss of lower motor neurons.
-
Muscle Atrophy at 0
At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.
-
Body Weight at 0
Body mass peaked at approximately 7 weeks of age (i.e., two weeks off dox) and then progressively dropped. Excessive loss of body weight (>30% decrease from peak weight) often defined end-stage.
-
Premature Death at 0
rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.
-
Gliosis at 0
Astrogliosis develops in many brain regions, including layer V of the motor cortex.
Absent
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Widespread cytoplasmic inclusions of TDP-43 in the brain and spinal cord. Ubiquitin-positive inclusions, loss of endogenous mouse nuclear TDP-43, cortical atrophy, motor neuron loss, astrogliosis, and NMJ denervation. |
A variety of motor impairments, including hindlimb clasping, fine tremor in forelimb and/or hindlimb, progressive loss of grip strength, and decline in coordinated movement and balance. |
ΔNLS-FUS x TDP-43(WT)
Observed
-
Motor Impairment at 8
Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire test.
-
Cortical Neuron Loss at 52
By 1 year, there was neuronal loss in the motor cortex.
-
Cytoplasmic Inclusions at 24
Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.
-
Body Weight at 48
Decreased by 48 weeks.
-
Premature Death at 60
Approximately 40% mortality by 60 weeks of age.
-
Gliosis at 52
Microgliosis and astrocytosis were observed in the motor cortex.
Absent
-
Lower Motor Neuron Loss at
Not observed at 1 year in the L5 anterior horn.
No Data
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| FUS, TARDBP | FUS ΔNLS | FUS: Transgenic; TARDBP: Transgenic | Amyotrophic Lateral Sclerosis | The motor cortex exhibited gliosis, a loss of neurons, and DNLS-FUS aggregates positive for ubiquitin and p62. |
Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test. |
TARDBP (A315T) (congenic)
Observed
-
Motor Impairment at 0
Deficits have been reported in nonspecific measures of strength and coordination such as the Rotarod (males and females) and hanging-wire test (males). A severely impaired gait (“swimming gait”) was observed in mice fed a gel diet.
-
Cytoplasmic Inclusions at 0
Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.
-
NMJ Abnormalities at 0
Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).
-
Muscle Atrophy at 0
Atrophy of gastrocnemius muscle (gel diet).
-
Body Weight at 0
Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.
-
Premature Death at 0
Survival is limited by severe gastrointestinal dysfunction and can be prolonged with a gel diet. Lifespan varies, but in general on a standard diet males live about 3 months and females about 6 months.
-
Gliosis at 0
Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.
Absent
-
Lower Motor Neuron Loss at
Most studies reported no lower motor neuron loss. One study observed 20% loss of large ventral horn neurons, possibly dependent on diet and how long the mice live in an individual colony.
No Data
-
Cortical Neuron Loss at
These mice lose corticospinal tract axons, but outright loss of cortical neurons has not been reported in the model. When crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, mice expressing TDP-43 (A315T) had fewer neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016).
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP A315T | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis | Minimal motor neuron loss in the spinal cord and cortex (but see Espejo-Porras et al., 2015 and Zhang et al., 2016). Ubiquitin-positive aggregates in upper and lower motor neurons. Rare TDP-43 aggregates. Astrocytosis in spinal cord and cortical layer V. Hyperexcitability of somatostatin interneurons. Axonal degeneration and ~ 20% loss of NMJ innervation (gel diet). |
Variable. Gait abnormalities, and impaired performance on the Rotarod. Also deficits in radial arm water maze, not due to deficits in swimming speed. Behavior potentially confounded by gut phenotype.
|
TARDBP (A315T) (hybrid)
Observed
-
Motor Impairment at 12
Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.
-
Cortical Neuron Loss at 18
By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.
-
Lower Motor Neuron Loss at 19
By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.
-
Cytoplasmic Inclusions at 21
By end-stage, cytoplasmic inclusions of ubiquitinated proteins in layer 5 neurons of motor, sensory, and cingulate cortex. Ubiquitin aggregates in ventral horn neurons. TDP-43 inclusions were rare.
-
Muscle Atrophy at 20
By end-stage, atrophic muscle fibers were observed.
-
Body Weight at 18
Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.
-
Premature Death at 22
Survival for about 5 months (154 ± 19 days) before dying spontaneously or being euthanized. It was not reported if this analysis includes males, females, or both.
-
Gliosis at 19
By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.
Absent
No Data
-
NMJ Abnormalities at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP A315T | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis | Upper and lower motor neuron loss. Cytoplasmic aggregates of ubiquitinated proteins in motor neurons. Cortical gliosis. No cytoplasmic aggregates of TDP-43. |
Gait abnormalities around three months, developing into a characteristic “swimming gait” by four to five months. |
Tardbp Q331K Knock-In
Observed
Absent
No Data
-
Motor Impairment at
No data.
-
Cortical Neuron Loss at
No data.
-
Lower Motor Neuron Loss at
No data.
-
Cytoplasmic Inclusions at
No data.
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
-
Body Weight at
No data.
-
Premature Death at
No data.
-
Gliosis at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| Tardbp | Tardp Q331K | Tardbp: Knock-In | Frontotemporal Dementia, Amyotrophic Lateral Sclerosis | Unknown. |
Unknown. |
Tardp LCDmut
Observed
-
Motor Impairment at 48
Grip strength in both male and female mice begins to decline at 12 months of age. By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles.
-
Lower Motor Neuron Loss at 96
28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with non-transgenic littermates.
-
Cytoplasmic Inclusions at 72
At 18 months of age, p62- and ubiquitin-positive inclusions are found in the ventral regions of the spinal cord, although these inclusions do not appear to be located in the cytoplasm of motor neurons.
-
NMJ Abnormalities at 96
By 24 months, a 15 percent reduction in motor units innervating the extensor digitorum muscle.
Absent
-
Premature Death at
Do not exhibit premature death, at least until 24 months of age.
No Data
-
Cortical Neuron Loss at
No data.
-
Muscle Atrophy at
No data.
-
Body Weight at
No data.
-
Gliosis at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| Tardbp | Tardbp M323K | Tardbp: Other | Frontotemporal Dementia, Amyotrophic Lateral Sclerosis | At 18 months of age, p62- and ubiquitin-positive inclusions in the ventral regions of the spinal cord, although apparently not in the cytoplasm of motor neurons. TDP-43 normally localized to the nucleus in 12-month mice. At 24 months, a 28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with control littermates. |
Grip strength in both male and female mice begins to decline at 12 months of age. |
Tardp_RRM2mut
Observed
Absent
-
Motor Impairment at
Not observed at 2 years.
-
Lower Motor Neuron Loss at
Not observed at 2 years.
-
Cytoplasmic Inclusions at
Not observed at 2 years.
-
NMJ Abnormalities at
Not observed at 2 years.
-
Premature Death at
Homozygous mutation is embryonic lethal.
No Data
-
Cortical Neuron Loss at
No data.
-
Muscle Atrophy at
No data.
-
Body Weight at
No data.
-
Gliosis at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| Tardbp | Tardp F210I | Tardbp: Other | Frontotemporal Dementia, Amyotrophic Lateral Sclerosis | No spinal motor neuron loss, no p62- or ubiquitin-positive inclusions at 2 years in heterozygotes. |
Grip strength normal at 2 years in heterozygotes. |
TDP-43 (A315T)
Observed
-
Motor Impairment at 38
At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.
-
Cytoplasmic Inclusions at 43
Cytoplasmic accumulation of TDP-43 was observed by 10 months of age in the spinal cord. Furthermore, cytoplasmic aggregates were observed and often co-localized with ubiquitin. These inclusions are not detected at three months of age.
-
Gliosis at 13
Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.
Absent
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
-
Premature Death at
Not observed.
No Data
-
NMJ Abnormalities at
Unknown.
-
Muscle Atrophy at
Unknown.
-
Body Weight at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP A315T | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Cytoplasmic inclusions of TDP-43, axonal changes, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. |
Age-associated cognitive and motor deficits as measured by the passive avoidance test and the Rotarod. |
TDP-43 (A315T) (line 23)
Observed
-
Motor Impairment at 0
Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.
-
Cytoplasmic Inclusions at 0
Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Cytoplasmic aggregates of TDP-43 are largely absent, although rare phospho-TDP-43 inclusions were observed, especially at end-stage.
-
Muscle Atrophy at 0
Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.
-
Body Weight at 0
Progressive weight loss.
-
Premature Death at 0
Line 23 mice survived about 2.5 months, mean survival 75 days. It was not reported whether this survival analysis includes males, females or both. Colony at Jackson Labs has longer mean survival.
-
Gliosis at 0
Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.
Absent
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
No Data
-
NMJ Abnormalities at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP A315T | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | No overt neuronal loss in the brain or spinal cord. Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Astrocytosis. Cytoplasmic aggregates of TDP-43 are largely absent, although some phospho-TDP-43 inclusions at end-stage. |
Progressive motor impairment characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs. |
TDP-43 (G348C)
Observed
-
Motor Impairment at 36
Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.
-
Cytoplasmic Inclusions at 43
Cytoplasmic accumulation of TDP-43 was observed by 10 months in the spinal cord. Cytoplasmic aggregates occurred and often co-localized with ubiquitin. These inclusions are not detected at 3 months of age.
-
NMJ Abnormalities at 43
In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.
-
Gliosis at 13
Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.
Absent
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
-
Premature Death at
Normal lifespan.
No Data
-
Muscle Atrophy at
Unknown.
-
Body Weight at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP G348C | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Cytoplasmic inclusions of TDP-43 in neurons, axonal changes, denervated NMJs, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. |
Age-associated cognitive and motor deficits as measured by the passive-avoidance test, the Barnes maze, and the Rotarod. |
TDP-43 (M337V)
Observed
-
Motor Impairment at 3
Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”
-
Cytoplasmic Inclusions at 0
TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.
-
Body Weight at 4
By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.
-
Premature Death at 5
70% mortality of homozygotes by around one month of age.
-
Gliosis at 0
Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.
Absent
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
No Data
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP M337V | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | No overt neuronal death. Microgliosis and astrogliosis. Abnormal mitochondria in the form of eosinophilic aggregates in spinal motor neurons. Widespread ubiquitination and accumulation of phospho-tau. |
Body tremors and gait difficulties before one month of age, leading to a “dragging” gait. An inability to right themselves precipitating euthanasia around one to two months of age. |
TDP-43 (M337V) (Mt-TAR6/6)
Observed
-
Motor Impairment at 2
Motor impairment developed quickly, by 11 days of age in homozygous mice, starting with an abnormal clasping reflex. They also develop a hunched posture, muscle twitches, and reduced mobility. Paralysis developed within days, leading to death. Hemizygotes do not develop motor symptoms until about one year of age, and impairment varied from mouse to mouse.
-
Cortical Neuron Loss at 2
Severe neuronal loss in all CA regions of the hippocampus of homozygous mice. Neuronal loss was also observed in layer V cortical neurons and thalamic neurons.
-
Lower Motor Neuron Loss at 2
Neuronal loss was observed in the spinal cords of homozygous mice.
-
Cytoplasmic Inclusions at 2
Some homozygous mice developed cytoplasmic inclusions in layer V cortical neurons. These were often, but not always, ubiquitin–positive. They were not universally observed, even in end-stage mice.
-
Body Weight at 2
Early postnatal growth retardation in homozygous mice. By day 17 their average body weight is about half that of non-Tg controls.
-
Premature Death at 2
Homozygous mice survived an average of just 17 days. In contrast, hemizygous Mt-TAR6 mice lived up to 24 months (average survival ~16.4 months).
-
Gliosis at 0
Elevated astrogliosis and microgliosis compared with non-Tg controls, especially in the motor cortex and spinal cord. Gliosis in the hippocampus was seen at end stage.
Absent
No Data
-
NMJ Abnormalities at
Unknown.
-
Muscle Atrophy at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP M337V | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Neuronal loss in cortical layer V motor neurons, spinal anterior horn motor neurons, CA regions of the hippocampus, and thalamic neurons. Astrogliosis and microgliosis. Diffuse cytoplasmic ubiquitin in cortical and spinal motor neurons and hippocampus, but rare overt inclusions. Deformed mitochondria and fission deficits. |
Progressive motor impairment, involving a hunched posture, muscle twitches, and reduced mobility. Impaired Rotarod performance. Complete paralysis and premature death. |
TDP-43 (Q331K)
Observed
-
Motor Impairment at 13
Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.
-
Lower Motor Neuron Loss at 8
Age-dependent loss of lower motor neurons in the lumbar spinal cord. Loss is detectable as early as 2 months of age and is more pronounced by 10 months.
-
NMJ Abnormalities at 43
Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.
-
Gliosis at 43
Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.
Absent
-
Cytoplasmic Inclusions at
TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.
No Data
-
Cortical Neuron Loss at
Unknown.
-
Muscle Atrophy at
Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.
-
Body Weight at
Unknown.
-
Premature Death at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP Q331K | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Age-dependent lower motor loss, gliosis, NMJ abnormalities and loss. No TDP-43 aggregates or cytoplasmic mislocalization. |
A variety of motor impairments starting around 3 months of age including tremor, abnormal hindlimb clasping, decreased Rotarod performance, and a later decrease in grip strength. |
TDP-43 (Q331K) Knock-In (Line 52)
Observed
-
Cortical Neuron Loss at 20
25% loss of parvalbumin-positive neurons at 5 months.
-
Body Weight at 32
Increased body weight.
-
Premature Death at 0
Mutation may be deleterious to male embryos.
Absent
-
Motor Impairment at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
-
Cytoplasmic Inclusions at
Not observed.
-
NMJ Abnormalities at
Not observed.
No Data
-
Muscle Atrophy at
Unknown.
-
Gliosis at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| Tardbp | Tardp Q331K | Tardbp: Knock-In | Frontotemporal Dementia, Amyotrophic Lateral Sclerosis | No TDP-43- or tau-positive inclusions. No apparent loss of upper or lower motor neurons, but 25% decrease in number of parvalbumin-positive neurons in frontal cortex. |
Attention deficits in a five-choice serial reaction time task, memory deficits in a novel-object-recognition task, deficits in a marble-burying task. No apparent motor impairments. |
TDP-43 (WT) (Elliott)
Observed
-
Motor Impairment at 0
Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.
-
Cytoplasmic Inclusions at 0
Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.
-
Muscle Atrophy at 0
An analysis of the quadriceps muscle
,showed signs of myopathy, including variable muscle fiber size and disorganization of the muscle architecture. -
Body Weight at 0
Progressive weight loss.
-
Premature Death at 16
The mean survival of hemizygous mice was 109 days (it is not clear if this value represents males, females, or both).
Absent
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
No Data
-
NMJ Abnormalities at
No data.
-
Gliosis at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis | No overt neuronal loss in the brain or spinal cord.
|
Progressive motor impairment (variable penetrance) starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. |
TDP-43 (WT) (Julien model)
Observed
-
Motor Impairment at 42
Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.
-
NMJ Abnormalities at 41
Some NMJ denervation was observed by 10 months of age. About 5% of NMJs at the gastrocnemius muscle were denervated, with another 20 percent partially denervated.
-
Gliosis at 12
Gliosis, both microgliosis and astrogliosis, occur early in the brain and spinal cord. Reactive glia were detected as early as 3 months of age, with more by 10 months.
Absent
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
-
Cytoplasmic Inclusions at
Primarily nuclear localization of human TDP-43.
No Data
-
Muscle Atrophy at
No data.
-
Body Weight at
No data.
-
Premature Death at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Some denervated NMJs, gliosis (microgliosis and astrogliosis), no overt neuronal loss or loss of axons. Mostly nuclear expression of TDP-43. |
Age-associated cognitive and motor deficits as measured by the passive avoidance test, Barnes maze, and Rotarod. |
TDP-43 (WT) (Kumar-Singh)
Observed
-
Motor Impairment at 2
Homozygous mice exhibit an abnormal clasping reflex by postnatal day 14. Other early motor deficits include a shortened stride, a wide stance, and frequent stumbling. By day 18, reduced performance on the Rotarod. Complete paralysis occurs ~10 days after onset.
-
Cortical Neuron Loss at 3
In homozygous mice, quantitative loss of neurons occurs in the motor cortex compared with non-Tg littermates. Both superficial and deep cortical layers of the anterior cortex are affected.
-
Lower Motor Neuron Loss at 3
By day 18, homozygous mice exhibited about 25 percent loss of motor neurons in the lumbar spinal cord compared with non-Tg littermates.
-
Cytoplasmic Inclusions at 3
Homozygous mice developed cytoplasmic inclusions in the brain and spinal cord, many of which were ubiquitin-positive. A minority of inclusions co-labeled with TDP-43. Ultrastructural analysis revealed ubiquitin–negative cytoplasmic inclusions in anterior horn neurons to be abnormal accumulations of mitochondria.
-
Body Weight at 0
Size and weight of homozygous mice lag behind hemizygotes and non-Tg littermates.
-
Premature Death at 3
Homozygous mice survive an average of just 24 days. In contrast, hemizygous mice survive to advanced age, although they die more prematurely than non-Tg mice, after 22 to 24 months.
-
Gliosis at 2
Astrogliosis and microgliois especially in cortical layer V of the anterior cortex, including motor and somatosensory cortex, and in the spinal cord.
Absent
No Data
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Neuronal loss in the brain and spinal cord, including anterior cortex, CA3 hippocampus, Purkinje cells, and spinal cord. Astrogliosis and microgliosis especially in the anterior cortex. Widespread diffuse ubiquitin in neurons of the brain and spinal cord, including cytoplasmic and nuclear inclusions, some co-labeling for TDP-43. |
Progressive motor impairment, starting at postnatal day 14, with an abnormal hindlimb reflex. Gait abnormalities, including reduced stride length and impaired performance on the accelerating Rotarod. Quick progression to muscle fasciculation’s and spasms, followed by paralysis and premature death. |
TDP-43 (WT) (Petrucelli)
Observed
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Motor Impairment at 3
By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.
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Cytoplasmic Inclusions at 4
Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.
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Body Weight at 2
Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.
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Premature Death at 5
Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.
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Gliosis at 4
Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.
Absent
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Cortical Neuron Loss at
Not observed.
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Lower Motor Neuron Loss at
Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.
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Muscle Atrophy at
Atrophy of the gastrocnemius muscle was not observed.
No Data
-
NMJ Abnormalities at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | No overt neuronal death, but degenerating neurites and axons, gliosis, and vacuolization of myelin. Abnormal aggregates of mitochondria present as eosinophilic aggregates in spinal motor neurons. Dendritic spine loss in the hippocampus. |
Homozygous mice develop body tremors and gait impairments leading to a “swimming gait” and severe motor deficits requiring euthanasia. |
TDP-43 (Wt-TAR6/6)
Observed
-
Motor Impairment at 6
Progressive motor impairment; abnormal hind limb reflexes observed as early as 1.5 months.
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Cortical Neuron Loss at 24
Approximate 15 percent loss of layer V neurons in motor cortex at 6 months.
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Lower Motor Neuron Loss at 12
Spinal motor neuron loss observed at 3 months, with approximately 10 percent fewer anterior horn neurons in lumbosacral regions at 6 months, compared with non-transgenic mice.
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Cytoplasmic Inclusions at 0
Inclusions containing phosphorylated TDP-43 rarely observed in the nuclei and cytoplasm of spinal neurons.
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Muscle Atrophy at 0
Muscle wasting, particularly in flanks.
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Body Weight at 13
TAR6/6 mice had lower body weights than non-transgenic mice between 3.25 and 3.75 months age, but the two genotypes were similar at younger and older ages (at least until 4.25 months).
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Premature Death at 27
Average survival is 6.7 months.
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Gliosis at 6
Microgliosis in cortex and spinal cord prominent at 6 months; astrogliosis in cortex and spinal cord apparent at 1.5 months.
Absent
No Data
-
NMJ Abnormalities at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| TARDBP | TARDBP: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Accumulation of transgenic and C-terminal fragments of TDP-43 in the cytoplasm, upper and lower motor neuron loss, astrogliosis, and microgliosis. |
Motor impairments as early as 6 weeks, reduced anxiety and disturbed nest-building behavior. |
ALS-related Research Models
- Sex-specific differences
- Cortical Neuron Loss
- Lower Motor Neuron Loss
- Cytoplasmic Inclusions
- Gliosis
- NMJ Abnormalities
- Muscle Atrophy
- Motor Impairment
- Body Weight
- Premature Death
NEFH-tTA x hTDP-43ΔNLS
Observed
Observed
Observed
Observed
Observed
Observed
Observed
Observed
Observed
TARDBP (A315T) (congenic)
No Data
Absent
Observed
Observed
Observed
Observed
Observed
Observed
Observed
TARDBP (A315T) (hybrid)
Observed
Observed
Observed
Observed
No Data
Observed
Observed
Observed
Observed
TDP-43 (A315T) (line 23)
Absent
Absent
Observed
Observed
No Data
Observed
Observed
Observed
Observed
TDP-43 (M337V) (Mt-TAR6/6)
Observed
Observed
Observed
Observed
No Data
No Data
Observed
Observed
Observed
TDP-43 (Q331K) Knock-In (Line 52)
Observed
Absent
Absent
No Data
Absent
No Data
Absent
Observed
Observed
TDP-43 (WT) (Kumar-Singh)
Observed
Observed
Observed
Observed
No Data
No Data
Observed
Observed
Observed