Role of Cortistatin in the immune changes associated with brain neurodegeneration in Huntington´s disease N. Adan1, R. Benitez1, M. Cherubini2, S. Gines3, M. Caro1, I. Forte-Lago1, E. Gonzalez-Rey1* 1Institute of Parasitology and Biomedicine (IPBLN-CSIC), Granada, Spain; 2University of Oxford, United Kingdom; 3University of Barcelona, Spain *Corresponding Author
Nervous and Immune systems interact through a common biochemical and cellular language that maintain homeostasis. Imbalances in this crosstalk can lead to different diseases. For example, in Huntington´s disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, patients shown high levels of circulating cytokines and exacerbated inflammatory response years before the disease onset. However, correlation between factors regulating this pro-inflammatory predisposition and neurodegeneration is unknown. Cortistatin (CST) is a neuropeptide produced by brain cortex and immune cells with an immunomodulatory and neuroprotective role. Interestingly, decreased levels of CST are found in animals with experimental autoimmune encephalomyelitis, in Alzheimer´s patients, and in the retina of diabetic patients, suggesting a relationship between CST reduction, inflammation and neurodegeneration. Thus, we investigate if CST could be influencing altered peripheral immune activation that underlies neurodegeneration in HD. We demonstrated that lack of CST induced an activated phenotype in peripheral immune cells, microglia and astrocytes, which showed deregulated responses to inflammatory stimulation. Moreover, naïve CST-deficient mice showed a prompted inflammatory state in periphery and nervous system with reduced levels of trophic factors. CST-deficient mice showed increased vulnerability to 3-nitropropionic acid toxin model of HD, with accelerated weight loss, reduced motor ability, increased mortality and augmented striatal gliosis. Interestingly, CST is decreased in target brain tissues of HdhQ111 mice (a murine HD model). CST reduction in Q111 striatal neurons seem to be related with a higher mortality and inflammatory activity under neurotoxic conditions. Analyzing existing expression databases, we have also showed that CST expression is reduced in peripheral immune cells of HD´s patients. These results identify CST as a key player in the nervous and immune bidirectional communication and pointed its potential as a new biomarker of neurodegenerative diseases with an immune component.
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