Altered CSF cytokine network in amyotrophic lateral sclerosis patients: A pathway-based statistical analysis

Martínez, Héctor R.; Escamilla-Ocañas, C.E.; Tenorio-Pedraza, Juan Miguel; Gómez‐Almaguer, David; Jaime‐Pérez, José Carlos; Olguín-Ramírez, Leticia A.; Salazar‐Marioni, Sergio; González‐Garza, María Teresa

doi:10.1016/j.cyto.2016.09.022

Cited by 18 publications

(13 citation statements)

References 21 publications

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“…A variety of pro-inflammatory cytokines and growth factors, including IL-5 and IL-15, have previously been reported to be elevated in cerebrospinal fluid of patients with ALS 53 and their abnormal expression has been associated with ALS clinical status 54 . PTGS2, IL6, and TNFα were similarly found dysregulated in ALS mouse models and patients, further supporting the relevance of our findings.…”

Section: Discussionmentioning

confidence: 99%

Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death

Ajmone‐Cat

Onori

Toselli

et al. 2019

Sci Rep

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Mutations of Fused in sarcoma (FUS), a ribonucleoprotein involved in RNA metabolism, have been found associated with both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). Notably, besides mutations in the coding sequence, also mutations into the 3′ untranslated region, leading to increased levels of the wild-type protein, have been associated with neuronal death and ALS pathology, in ALS models and patients. The mechanistic link between altered FUS levels and ALS-related neurodegeneration is far to be elucidated, as well as the consequences of elevated FUS levels in the modulation of the inflammatory response sustained by glial cells, a well-recognized player in ALS progression. Here, we studied the effect of wild-type FUS overexpression on the responsiveness of mouse and human neural progenitor-derived astrocytes to a pro-inflammatory stimulus (IL1β) used to mimic an inflammatory environment. We found that astrocytes with increased FUS levels were more sensitive to IL1β, as shown by their enhanced expression of inflammatory genes, compared with control astrocytes. Moreover, astrocytes overexpressing FUS promoted neuronal cell death and pro-inflammatory microglia activation. We conclude that overexpression of wild-type FUS intrinsically affects astrocyte reactivity and drives their properties toward pro-inflammatory and neurotoxic functions, suggesting that a non-cell autonomous mechanism can support neurodegeneration in FUS-mutated animals and patients.

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Section: Discussionmentioning

confidence: 99%

Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death

Ajmone‐Cat

Onori

Toselli

et al. 2019

Sci Rep

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“…IL-4 levels have been reported to be negatively correlated with IL-6 levels in cerebrospinal fluid of ALS cases. Thus, if IL-6 level increases, IL-4 decreases [44]. In vitro , ASH restored LPS-induced downregulation of microglial IL-4 secretion and thus may contribute to modulation of inflammatory processes in multiple ways.…”

Section: Discussionmentioning

confidence: 99%

Withania somnifera Reverses Transactive Response DNA Binding Protein 43 Proteinopathy in a Mouse Model of Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration

et al. 2017

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Abnormal cytoplasmic mislocalization of transactive response DNA binding protein 43 (TARDBP or TDP-43) in degenerating neurons is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous work suggested that nuclear factor kappa B (NF-κB) may constitute a therapeutic target for TDP-43-mediated disease. Here, we investigated the effects of root extract of Withania somnifera (Ashwagandha), an herbal medicine with anti-inflammatory properties, in transgenic mice expressing a genomic fragment encoding human TDP-43A315T mutant. Ashwagandha extract was administered orally to hTDP-43A315T mice for a period of 8 weeks starting at 64 and 48 weeks of age for males and females, respectively. The treatment of hTDP-43A315T mice ameliorated their motor performance on rotarod test and cognitive function assessed by the passive avoidance test. Microscopy examination of tissue samples revealed that Ashwagandha treatment of hTDP-43A315T mice improved innervation at neuromuscular junctions, attenuated neuroinflammation, and reduced NF-κB activation. Remarkably, Ashwagandha treatment reversed the cytoplasmic mislocalization of hTDP-43 in spinal motor neurons and in brain cortical neurons of hTDP-43A315T mice and it reduced hTDP-43 aggregation. In vitro evidence is presented that the neuronal rescue of TDP-43 mislocalization may be due to the indirect effect of factors released from microglial cells exposed to Ashwagandha. These results suggest that Ashwagandha and its constituents might represent promising therapeutics for TDP-43 proteinopathies.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-016-0499-2) contains supplementary material, which is available to authorized users.

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“…In an attempt to deal with this issue, some authors have proposed that it would be more appropriate to identify panels of biomarkers, rather than focusing on a single target [87,88]. In this sense, panels of cytokines have been analyzed to help in a more accurate prediction of disease progression [89,90]. However, some authors suggest that these promising multivariate models should also include other clinical parameters, such as ALS type (sporadic or familial), disease stage, anatomical onset of motor neuron impairment and even age and gender [26,91].…”

Section: Cytokines As Biomarkers: Main Challengesmentioning

confidence: 99%

Are Circulating Cytokines Reliable Biomarkers for Amyotrophic Lateral Sclerosis?

Moreno-Martínez

Calvo

Muñoz

et al. 2019

IJMS

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has no effective treatment. The lack of any specific biomarker that can help in the diagnosis or prognosis of ALS has made the identification of biomarkers an urgent challenge. Multiple panels have shown alterations in levels of numerous cytokines in ALS, supporting the contribution of neuroinflammation to the progressive motor neuron loss. However, none of them is fully sensitive and specific enough to become a universal biomarker for ALS. This review gathers the numerous circulating cytokines that have been found dysregulated in both ALS animal models and patients. Particularly, it highlights the opposing results found in the literature to date, and points out another potential application of inflammatory cytokines as therapeutic targets.

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Altered CSF cytokine network in amyotrophic lateral sclerosis patients: A pathway-based statistical analysis

Cited by 18 publications

References 21 publications

Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death

Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death

Withania somnifera Reverses Transactive Response DNA Binding Protein 43 Proteinopathy in a Mouse Model of Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration

Are Circulating Cytokines Reliable Biomarkers for Amyotrophic Lateral Sclerosis?

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