Microglial cathepsin B promotes neuronal efferocytosis during brain development

Area of Science:

• Neuroscience
• Cell Biology
• Developmental Biology

Background:

• Microglia, the brain's immune cells, perform efferocytosis, clearing apoptotic cells during neural development.
• While microglial recognition of apoptotic cells is studied, the lysosomal mechanisms for efficient digestion remain unclear.

Purpose of the Study:

• To investigate the role of the lysosomal protease cathepsin B in microglial efferocytosis of neurons.
• To understand how cathepsin B influences apoptotic cell clearance and brain development.

Main Methods:

• Investigated cathepsin B expression in microglia in zebrafish and mouse models.
• Utilized myeloid-specific cathepsin B knockdown in zebrafish and global cathepsin B deficiency in mice.
• Employed live imaging of microglia and neuronal apoptosis markers.

Main Results:

• Cathepsin B is microglia-specific and highly expressed in areas of high neuronal turnover.
• Knockdown or deficiency of cathepsin B resulted in undigested apoptotic cells within microglia and tissue accumulation.
• Impaired phagolysosomal fusion, acidification, and delayed phagocytosis resolution were observed.
• Behavioral impairments were noted in both zebrafish and mouse models.

Conclusions:

• Microglial cathepsin B is essential for efficient neuronal efferocytosis during brain development.
• Cathepsin B deficiency leads to impaired apoptotic cell clearance, affecting neural development and behavior.
• This study identifies a novel role for cathepsin B in lysosomal function critical for microglial efferocytosis.