Species: Mouse
Genes: C9orf72
Modification: C9orf72: Knock-Out
Disease Relevance: Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
Strain Name: 3110043O21Riktm1(KOMP)Mbp
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Motor Impairment
Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.
Last Updated: 03 Jun 2016
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Knock-Out
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: N/A
Summary
Last Updated: 15 Apr 2016
Further Reading
No Available Further Reading
Overview
Name: Xaliproden
Synonyms: SR 57746A
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Sanofi
Background
Xaliproden is an orally active 5HT1-A receptor antagonist that was being developed by Sanofi. It has been evaluated for the treatment of Alzheimer's disease and amyotrophic lateral sclerosis (ALS), and protection against peripheral neurotoxicity associated with certain cancer chemotherapies.
The rationale behind this approach was that blocking the 5HT1-A receptor might enhance cognition by stimulating release of acetylcholine and glutamate (Schechter et al., 2002). Xaliproden was variously reported to have antidepressant or neuroprotective/neurotrophic effects in rats, cultured cells, and various mouse models (e.g. Cervo et al., 1994; Pradines et al., 1995; Lemaire et al., 2002; Appert-Collin et al., 2004). It has been reported to counteract Aβ-induced neuronal toxicity and memory deficits in rats (Terranova et al., 1996) and to have beneficial effects in cell-based and animal models of motor neuron disease and multiple sclerosis.
Findings
No public record exists of Phase 2 trials of this compound in AD. Between 2003 and 2007, Sanofi conducted two 18-month Phase 3 trials in mild-to-moderate Alzheimer's disease, one enrolling 1,455 patients, the other 1,306. No treatment effect was found on the ADAS-cog or CDR. One study reported reduced hippocampal atrophy in a subgroup.
Two Phase 3 trials conducted in 867 and 1,210 patients with ALS, respectively, found no statistically significant treatment benefit. Full results were reported (Meininger et al., 2004).
This program was discontinued in 2007 (Porzner et al., 2009; Sabbagh, 2009). For all studies on Xaliproden in Alzheimer's see clinicaltrials.gov.
Last Updated: 11 Mar 2016
Further Reading
No Available Further Reading
Species: Mouse
Genes: SOD1
Modification: SOD1: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: B6SJL-Tg(G93A-SOD1)1Gur/J
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Cortical Neuron Loss
Although outright upper motor neuron loss is absent or rare, degenerative signs (e.g., swollen neurites, Gallyas-positive aggregates, vacuoles, and neuritic spheroids) have been shown in motor regions of the cerebral cortex by five months of age.
Lower Motor Neuron Loss
Up to 50% loss of motor neurons in the cervical and lumbar segments of the spinal cord at end stage.
Cytoplasmic Inclusions
Inclusions accumulate in spinal motor neurons starting around 82 days of age. Inclusions generally take the form of spheroids or Lewy-body-like inclusions and commonly include a variety of neuronal intermediate filament proteins. TDP-43-positive inclusions are not present.
Gliosis
Gliosis, including the proliferation of reactive microglia and astrocytes, develops in parallel with motor neuron degeneration in the spinal cord.
NMJ Abnormalities
Neuromuscular junctions degenerate around 47 days of age; fast-fatiguable motor neurons are affected first.
Muscle Atrophy
Longitudinal MRI has shown reduced muscle volume as early as 8 weeks of age. Atrophy is progressive. Skeletal muscle is affected, including limb and diaphragm.
Motor Impairment
Signs of motor impairment begin at about 3 months of age with a shaking tremor that leads to paralysis.
Body Weight
One of the first signs of illness is a slowing of growth and a plateauing of weight.
Premature Death
G1H mice reach end-stage disease by 5 months of age. Females typically survive longer than males.
Last Updated: 03 Apr 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: SOD1
Modification: SOD1: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Lower Motor Neuron Loss
Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.
Cytoplasmic Inclusions
Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.
Gliosis
Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.
NMJ Abnormalities
Denervation of muscle fibers is observed.
Muscle Atrophy
Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.
Motor Impairment
Progressive motor impairment generally starting around 8 months with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis within about two weeks.
Body Weight
Hemizygous mice start to lose weight at about 9 months of age.
Premature Death
End stage is characterized by paralysis at about 10 months of age.
Last Updated: 04 Jun 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: TARDBP
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Cortical Neuron Loss
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).
Lower Motor Neuron Loss
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.
Cytoplasmic Inclusions
Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.
Gliosis
Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.
NMJ Abnormalities
Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).
Muscle Atrophy
Atrophy of gastrocnemius muscle (gel diet).
Motor Impairment
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.
Body Weight
Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.
Premature Death
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.
Last Updated: 14 Mar 2018
Further Reading
No Available Further Reading
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