Molecular Neurobiology

, Volume 55, Issue 5, pp 4207–4224 | Cite as

Downregulated Glia Interplay and Increased miRNA-155 as Promising Markers to Track ALS at an Early Stage

  • Carolina Cunha
  • Catarina Santos
  • Cátia Gomes
  • Adelaide Fernandes
  • Alexandra Marçal Correia
  • Ana Maria Sebastião
  • Ana Rita Vaz
  • Dora Brites


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown cause. Absence of specific targets and biomarkers compromise the development of new therapeutic strategies and of innovative tools to stratify patients and assess their responses to treatment. Here, we investigate changes in neuroprotective-neuroinflammatory actions in the spinal cord of SOD1 G93A mice, at presymptomatic and symptomatic stages to identify stage-specific biomarkers and potential targets. Results showed that in the presymptomatic stage, there are alterations in both astrocytes and microglia, which comprise decreased expression of GFAP and S100B and upregulation of GLT-1, as well as reduced expression of CD11b, M2-phenotype markers, and a set of inflammatory mediators. Reduced levels of Connexin-43, Pannexin-1, CCL21, and CX3CL1 further indicate the existence of a compromised intercellular communication. In contrast, in the symptomatic stage, increased markers of inflammation became evident, such as NF-κB/Nlrp3-inflammasome, Iba1, pro-inflammatory cytokines, and M1-polarizion markers, together with a decreased expression of M2-phenotypic markers. We also observed upregulation of the CX3CL1-CX3CR1 axis, Connexin-43, Pannexin-1, and of microRNAs (miR)-124, miR-125b, miR-146a and miR-21. Reduced motor neuron number and presence of reactive astrocytes with decreased GFAP, GLT-1, and GLAST further characterized this inflammatory stage. Interestingly, upregulation of miR-155 and downregulation of MFG-E8 appear as consistent biomarkers of both presymptomatic and symptomatic stages. We hypothesize that downregulated cellular interplay at the early stages may represent neuroprotective mechanisms against inflammation, SOD1 aggregation, and ALS onset. The present study identified a set of inflamma-miRNAs, NLRP3-inflammasome, HMGB1, CX3CL1-CX3CR1, Connexin-43, and Pannexin-1 as emerging candidates and promising pharmacological targets that may represent potential neuroprotective strategies in ALS therapy.


Inflamma-miRNAs Transgenic SOD1G93A mice Presymptomatic and symptomatic stages Astrocytes and microglia function Motor neuron-glia communication ALS biomarkers 



Amyotrophic lateral sclerosis


Arginase 1


CCAAT/enhancer-binding protein alpha


Chemokine (C-C motif) ligand 21


Chemokine (C-C motif) receptor type 7


Cerebrospinal fluid


Chemokine (C-X3-C motif) ligand 1


Chemokine (C-X3-C motif) receptor 1




Glial fibrillary acidic protein


Glutamate transporter 1


Found in inflammatory zone 1


High mobility group box 1




Ionized calcium-binding adapter molecule 1






Milk fat globule-EGF factor 8


Neuronal nuclei


Nuclear factor kappa B


NOD-like receptor family pyrin domain containing 3




Phosphate buffer saline


Phosphorylated NF-κB


Quantitative reverse transcription polymerase chain reaction


Room temperature


S100 calcium-binding protein B


Spinal cord


Suppressor of cytokine signaling 1


Superoxide dismutase 1


Toll-like receptors


Transforming growth factor beta


Tumor necrosis factor alfa


Western blot


Wild type



This work was funded by the Research Grant of the Santa Casa Scientific Research Program on ALS, by Santa Casa da Misericórdia de Lisboa (SCML), Portugal, Project Ref. ELA-2015-002 (to DB), by the project PTDC/SAU-FAR/118787/2010 (to D.B.) and, in part, by iMed.ULisboa (UID/DTP/04138/2013) from Fundação para a Ciência e a Tecnologia (FCT). A.R.V. holds a postdoctoral research fellowship (SFRH/BPD/76590/2011), and C.C. and C.G. are recipients of PhD fellowships (SFRH/BD/91316/2012 and SFRH/BD/102718/2014, respectively), all from FCT. The funding organization had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank to Dr. Rui Gomes (Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal) for genotyping mice.

Author’s Contributions

D.B, conceived the study; D.B. and A.R.V. designed the experiments; A.R.V. gave technical support; C.C., C.G., A.R.V., A.F. and C.S. acquired data; A.S. and A.M.C. contributed to conceptual advice and data acquisition on mice related with its usage, management, and maintenance; A.R.V., C.C., and D.B. analyzed data; C.C. and A.R.V. drafted figures and participated in the manuscript writing; D.B. wrote and edited the final version. The manuscript has been read and approved by all named authors.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2017_631_MOESM1_ESM.doc (54 kb)
Supplementary Table 1 (DOC 53 kb)
12035_2017_631_MOESM2_ESM.doc (66 kb)
Supplementary Table 2 (DOC 66 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Neuron Glia Biology in Health and Disease Group, Research Institute for Medicines (iMed.ULisboa), Faculty of PharmacyUniversidade de LisboaLisbonPortugal
  2. 2.Department of Biochemistry and Human Biology, Faculty of PharmacyUniversidade de LisboaLisbonPortugal
  3. 3.Museu Nacional de História Natural e da CiênciaUniversidade de LisboaLisbonPortugal
  4. 4.Instituto de Farmacologia e Neurociências, Faculdade de MedicinaUniversidade de LisboaLisboaPortugal
  5. 5.Instituto de Medicina Molecular, Faculdade de MedicinaUniversidade de LisboaLisboaPortugal

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