Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression

Jeyachandran, Amilia; Mertens, Benjamin; McKissick, Eric A.; Mitchell, Cassie S.

doi:10.3389/fncel.2015.00462

Cited by 27 publications

(27 citation statements)

References 91 publications

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“…The physically long motoneurons have already been shown to be vulnerable to instability in both physiological and pathological ALS animal models, including the presence of destabilizing somatic dynamics ( 27 ), axonal transport deregulation ( 28 ), metabolic insufficiency ( 29 ), inadequate calcium buffering ( 29 ), compensatory oxidative stress responses ( 29 ), and dynamic imbalances of pro- and anti-inflammatory cytokines ( 30 ). Mathematical oscillations and corresponding instabilities have also been identified in theoretical ALS models ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Antecedent Disease and Amyotrophic Lateral Sclerosis: What Is Protecting Whom?

2016

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Multiple studies have shown that antecedent diseases are less prevalent in amyotrophic lateral sclerosis (ALS) patients than the general age-matched population, which suggests possible neuroprotection. Antecedent disease could be protective against ALS or, conversely, the asymptomatic early physiological underpinnings of ALS could be protective against other antecedent disease. Elucidating the impact of antecedent disease on ALS is critical for assessing diagnostic risk factors, prognostic outcomes, and intervention timing. The objective of this study was to examine the relationship between antecedent conditions and ALS onset age and disease duration (i.e. survival). Medical history surveys for 1439 Emory ALS Clinic patients (Atlanta, GA, USA) were assessed for antecedent hypertension, hyperlipidemia, diabetes, obesity, asthma, arthritis, chronic obstructive pulmonary disease (COPD), thyroid, kidney, liver, and other non-ALS neurological diseases. The ALS onset age and disease duration are compared between the antecedent and non-antecedent populations using chi square, Kaplan–Meier, and ordinal logistic regression. When controlled for confounders, antecedent hypertension (high blood pressure), hyperlipidemia (high cholesterol), arthritis, COPD, thyroid disease, and non-ALS neurological disease are found to be statistically associated with a delayed ALS onset age, whereas antecedent obesity [body mass index (BMI) > 30] was correlated to earlier ALS onset age. With the potential exceptions of liver disease and diabetes (the latter without other common comorbid conditions), antecedent disease is associated with overall shorter ALS disease duration. The unique potential relationship between antecedent liver disease and longer ALS disease duration warrants further investigation, especially given liver disease was found to be a factor of 4–7 times less prevalent in ALS. Notably, most conditions associated with delayed ALS onset are also associated with shorter disease duration. Pathological homeostatic instability exacerbated by hypervigilant regulation (over-zealous homeostatic regulation due to too high regulatory feedback gains) is a viable hypothesis for explaining the early-life protection against antecedent disease and the overall lower antecedent disease prevalence in ALS patients; the later ALS onset age in patients with antecedent disease; and the inverse relationship between ALS onset age and disease duration.

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Section: Discussionmentioning

confidence: 99%

Antecedent Disease and Amyotrophic Lateral Sclerosis: What Is Protecting Whom?

2016

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“…Moreover, a considerable number of case reports and pilot studies have indicated the beneficial effects of tocilizumab on other autoimmune and chronic inflammatory diseases [ 12 ]. Interestingly, as summarized in a recent meta-analysis [ 13 ], several studies indicated that IL-6 is elevated in the spinal cord of the mouse ALS model [ 14 , 15 ]. In addition, a previous report showed that IL-6 is increased in the cerebrospinal fluid of ALS patients [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 Deficiency Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutation

et al. 2016

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Background & AimAmyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease. Recent evidence indicates that inflammation is associated with many neurodegenerative diseases including ALS. Previously, abnormal levels of inflammatory cytokines including IL-1β, IL-6 and TNF-α were described in ALS patients and/or in mouse ALS models. In addition, one study showed that blocking IL-1β could slow down progression of ALS-like symptoms in mice. In this study, we examined a role for IL-6 in ALS, using an animal model for familial ALS.MethodsMice with mutant SOD1 (G93A) transgene, a model for familial ALS, were used in this study. The expression of the major inflammatory cytokines, IL-6, IL-1β and TNF-α, in spinal cords of these SOD1 transgenic (TG) mice were assessed by real time PCR. Mice were then crossed with IL-6(-/-) mice to generate SOD1TG/IL-6(-/-) mice. SOD1 TG/IL-6(-/-) mice (n = 17) were compared with SOD1 TG/IL-6(+/-) mice (n = 18), SOD1 TG/IL-6(+/+) mice (n = 11), WT mice (n = 15), IL-6(+/-) mice (n = 5) and IL-6(-/-) mice (n = 8), with respect to neurological disease severity score, body weight and the survival. We also histologically compared the motor neuron loss in lumber spinal cords and the atrophy of hamstring muscles between these mouse groups.ResultsLevels of IL-6, IL-1β and TNF-α in spinal cords of SOD1 TG mice was increased compared to WT mice. However, SOD1 TG/IL-6(-/-) mice exhibited weight loss, deterioration in motor function and shortened lifespan (167.55 ± 11.52 days), similarly to SOD1 TG /IL-6(+/+) mice (164.31±12.16 days). Motor neuron numbers and IL-1β and TNF-α levels in spinal cords were not significantly different in SOD1 TG /IL-6(-/-) mice and SOD1 TG /IL-6 (+/+) mice.ConclusionThese results provide compelling preclinical evidence indicating that IL-6 does not directly contribute to motor neuron disease caused by SOD1 mutations.

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“…Based on these promising anti-in ammatory effects in the APP/PS1 AD mouse model, we decided to continue the treatment in another mouse model of a neurodegenerative disorder in which neuroin ammation is known as main driver of the disease. Therefore, the SOD1*G93A ALS mouse model was chosen [17,18,26,54]. SOD1*G93A mice were treated intraperitoneally for 28 days with RD2RD2 or placebo.…”

Section: Discussionmentioning

confidence: 99%

“…In a non-pathological state, a complex signalling cascade produces a protective immune response through cytokines [22,23]. A temporal increased level of in ammatory cytokines was observed in ALS, but also in AD [24][25][26]. Like many other neurodegenerative diseases, such as AD, to date there is no curative therapy for ALS.…”

Section: Introductionmentioning

confidence: 99%

A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an Als Mouse Model

Post

Kogel

Schaffrath

et al. 2020

Preprint

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Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in brain stem and spinal cord. The cause is unknown, but an increasing evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe two treatment studies demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of Alzheimer’s disease (APP/PS1) and in a transgenic mouse model of ALS (SOD1*G93A).Methods:APP/PS1 and SOD1*G93A mice were treated intraperitoneally for four weeks mice with RD2RD2 vs placebo. APP/PS1 brain and plasma samples were histologically and biochemically analysed for inflammatory markers, gliosis and amyloid pathology. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration.Results: Treatment in APP/PS1 mice revealed significant reduction in glial cell activation in the brain and significantly lower levels of inflammatory cytokines in plasma. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both brain stem and lumbar spinal cord but also in a rescue of neurons in the motor cortex. Moreover, behavioural tests revealed that the disease phenotype of SOD1*G93A mice is halted during treatment.Conclusion: Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

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Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression

Cited by 27 publications

References 91 publications

Antecedent Disease and Amyotrophic Lateral Sclerosis: What Is Protecting Whom?

Antecedent Disease and Amyotrophic Lateral Sclerosis: What Is Protecting Whom?

Interleukin-6 Deficiency Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutation

A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an Als Mouse Model

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