Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• Microglia, the brain's immune cells, have unique developmental functions, but their activation regulation is unclear.
• Neuroinflammation in preterm infants' developing brains is linked to permanent neurological damage in millions annually.
• Understanding microglial activation is crucial for addressing neonatal brain injury.

Purpose of the Study:

• To investigate regulators of microglial activation in the developing brain.
• To determine the role of Wnt/β-catenin signaling in neuroinflammation-mediated injury.
• To explore Wnt pathway as a therapeutic target for neonatal brain injury.

Main Methods:

• Analysis of genes and proteins in mouse, zebrafish, and primary human/mouse microglia models.
• Genomic variation analysis in a cohort of preterm infants.
• In vivo studies using Wnt agonist delivered via microglia-specific nanocarriers.

Main Results:

• Reduced Wnt/β-catenin signaling drives a microglial phenotype causing hypomyelination.
• Genomic variations in the Wnt pathway correlate with brain connectivity in preterm infants.
• Wnt agonist therapy prevented pro-inflammatory microglial activation, white matter injury, and behavioral deficits in animal models.

Conclusions:

• The Wnt pathway is a key regulator of microglial activation in the developing brain.
• Wnt pathway dysregulation is critical in the pathogenesis of a significant form of human brain injury.
• Targeting the Wnt pathway presents a viable therapeutic strategy for neonatal brain injury.