Research Paper Volume 13, Issue 19 pp 22710—22731
Neurovascular dysfunction and neuroinflammation in a Cockayne syndrome mouse model
- 1 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
- 2 Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
- 3 Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
- 4 Rodent Histopathology Core, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
Received: July 23, 2021 Accepted: September 20, 2021 Published: October 10, 2021https://doi.org/10.18632/aging.203617
How to Cite
Copyright: © 2021 Kajitani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Cockayne syndrome (CS) is a rare, autosomal genetic disorder characterized by premature aging-like features, such as cachectic dwarfism, retinal atrophy, and progressive neurodegeneration. The molecular defect in CS lies in genes associated with the transcription-coupled branch of the nucleotide excision DNA repair (NER) pathway, though it is not yet clear how DNA repair deficiency leads to the multiorgan dysfunction symptoms of CS. In this work, we used a mouse model of severe CS with complete loss of NER (Csa−/−/Xpa−/−), which recapitulates several CS-related phenotypes, resulting in premature death of these mice at approximately 20 weeks of age. Although this CS model exhibits a severe progeroid phenotype, we found no evidence of in vitro endothelial cell dysfunction, as assessed by measuring population doubling time, migration capacity, and ICAM-1 expression. Furthermore, aortas from CX mice did not exhibit early senescence nor reduced angiogenesis capacity. Despite these observations, CX mice presented blood brain barrier disruption and increased senescence of brain endothelial cells. This was accompanied by an upregulation of inflammatory markers in the brains of CX mice, such as ICAM-1, TNFα, p-p65, and glial cell activation. Inhibition of neovascularization did not exacerbate neither astro- nor microgliosis, suggesting that the pro-inflammatory phenotype is independent of the neurovascular dysfunction present in CX mice. These findings have implications for the etiology of this disease and could contribute to the study of novel therapeutic targets for treating Cockayne syndrome patients.