| Literature DB >> 31665242 |
Juliette Van Steenwinckel1,2, Anne-Laure Schang1,2,3, Michelle L Krishnan4, Vincent Degos1,2,5, Andrée Delahaye-Duriez1,6, Cindy Bokobza1,2, Zsolt Csaba1,2, Franck Verdonk7,8, Amélie Montané1,2, Stéphanie Sigaut1,2, Olivier Hennebert1,2,9, Sophie Lebon1,2, Leslie Schwendimann1,2, Tifenn Le Charpentier1,2, Rahma Hassan-Abdi1,2, Gareth Ball4, Paul Aljabar4, Alka Saxena10, Rebecca K Holloway11, Walter Birchmeier12, Olivier Baud1,2, David Rowitch13, Veronique Miron11, Fabrice Chretien6,7,14, Claire Leconte15, Valérie C Besson15, Enrico G Petretto16, A David Edwards4, Henrik Hagberg4,17, Nadia Soussi-Yanicostas1,2, Bobbi Fleiss1,2,4,18, Pierre Gressens1,2,4.
Abstract
Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.Entities:
Keywords: 3DNA; innate immunity; neonatal encephalopathy; neuroinflammation; neuroprotection
Mesh：
Year: 2019 PMID： 31665242 PMCID： PMC6906599 DOI： 10.1093/brain/awz319
Source DB: PubMed Journal: Brain ISSN： 0006-8950 Impact factor: 13.501