Neurodegeneration by activation of the microglial complement-phagosome pathway

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Systemic inflammation is suspected to worsen neurodegenerative diseases through microglial activation.
• Microglia play a crucial role in brain immune responses and disease pathogenesis.

Purpose of the Study:

• To investigate the impact of repeated systemic inflammation on neurodegeneration.
• To elucidate the mechanisms underlying inflammation-induced neuronal loss, focusing on microglial activation and the complement system.

Main Methods:

• Mice were subjected to repeated systemic lipopolysaccharide (LPS) challenges over four days.
• Whole-genome transcriptome analysis was performed on brain tissue.
• Neurodegeneration was assessed, and complement C3-deficient mice were used to evaluate the complement system's role.

Main Results:

• Repeated LPS administration, unlike a single dose, induced a sustained microglial inflammatory phenotype and dopaminergic neuron loss in the substantia nigra.
• Transcriptome analysis revealed activation of the classical complement system and phagosome pathway.
• The loss of dopaminergic neurons was significantly reduced in complement C3-deficient mice.

Conclusions:

• Repeated systemic inflammation triggers a microglial inflammatory response involving the complement system and phagosome pathway.
• This inflammatory cascade leads to complement-mediated loss of dopaminergic neurons.
• The findings identify a novel mechanism contributing to neurodegeneration.