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Updated: Jul 21, 2025
A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
The cholesterol depleting agent, (2-Hydroxypropyl)-ß-cyclodextrin, does not affect disease progression in SOD1G93A
Linda Greensmith1,2, J Barney Bryson1,2
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.
Objective:
Previously, we demonstrated that Amyloid Precursor Protein (APP) contributes to pathology in the SOD1G93A mouse model of ALS and that genetic ablation of APP in SOD1G93A mice significantly improved multiple disease parameters, including muscle innervation and motor neuron survival. We also observed elevated levels of potentially neurotoxic Aß peptides that have been implicated in Alzheimer's Disease (AD) pathogenesis, within motor neurons and astrocytes in SOD1G93A mice. More recently, it has been shown that blocking Aß production improves outcome measures in SOD1G93A mice. The cyclodextrin, (2-Hydroxypropyl)-ß-cyclodextrin (HP-β-CD), has previously been shown to deplete intraneuronal unesterified cholesterol, resulting in effective reduction of Aß production and amelioration of disease progression in mouse models of AD and Niemann Pick Type C (NPC) disease. Here, we tested whether HP-β-CD could also improve phenotypic progression in SOD1G93A mice.
Methods:
Pre-symptomatic male SOD1G93A mice were randomly assigned to the following treatment groups: HP-β-CD (4000mg/kg, n = 9) or vehicle (saline; n = 10), delivered by weekly subcutaneous injection, commencing at 67 days of age. Longitudinal grip-strength and body mass analysis was performed until late-stage disease (120 days of age), followed by in vivo bilateral isometric muscle tension analysis of tibialis anterior (TA) and extensor digitorum longus (EDL) muscles. Results: HP-β-CD administration had no effect on body mass or grip-strength compared to vehicle treated SOD1G93A mice. Similarly, HP-β-CD treatment had no effect on muscle force, contractile properties or motor unit number estimates (MUNE) at late-stage disease in SOD1G93A mice.
Conclusion:
This study shows that HP-β-CD does not confer any therapeutic benefit in SOD1G93A mice. However, the absence of detrimental effects is informative, given the common use of cyclodextrins as complexing agents for other pharmaceutical products, their standalone therapeutic potential and the emerging association between dyslipidaemia and ALS progression.
Insights
(2-Hydroxypropyl)-ß-cyclodextrin (HP-β-CD) did not improve outcomes in the SOD1G93A mouse model of ALS. This study found no therapeutic benefit of HP-β-CD in ALS mice, but also no detrimental effects.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Amyloid Precursor Protein (APP) pathology and Aß peptides contribute to motor neuron degeneration in the SOD1G93A mouse model of Amyotrophic Lateral Sclerosis (ALS).
- Blocking Aß production has shown therapeutic potential in ALS mouse models.
- (2-Hydroxypropyl)-ß-cyclodextrin (HP-β-CD) reduces Aß production by depleting intraneuronal cholesterol in Alzheimer's Disease and Niemann Pick Type C models.
Purpose of the Study:
- To investigate the therapeutic efficacy of HP-β-CD in the SOD1G93A mouse model of ALS.
- To determine if HP-β-CD administration can improve disease progression and motor function in SOD1G93A mice.
Main Methods:
- Pre-symptomatic male SOD1G93A mice received weekly subcutaneous injections of HP-β-CD (4000mg/kg) or vehicle (saline).
- Longitudinal assessments included grip strength and body mass until 120 days of age.
- In vivo muscle tension analysis of tibialis anterior and extensor digitorum longus muscles, and motor unit number estimates (MUNE) were performed.
Main Results:
- HP-β-CD treatment showed no significant effect on body mass or grip strength compared to vehicle-treated controls.
- Muscle force, contractile properties, and MUNE remained unaffected by HP-β-CD administration in late-stage SOD1G93A mice.
- No detrimental effects were observed with HP-β-CD treatment.
Conclusions:
- HP-β-CD does not provide therapeutic benefits for phenotypic progression in the SOD1G93A mouse model of ALS.
- The lack of adverse effects is noteworthy given the widespread use of cyclodextrins in pharmaceutical formulations.
- Further research may explore the role of dyslipidemia in ALS progression, as HP-β-CD targets cholesterol metabolism.
