Berberine modulates microglial polarization by activating TYROBP in Alzheimer's disease.

Background: Characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles, and aberrant neuroinflammation in the brain, Alzheimer's disease (AD) is the most common neurodegenerative disease. Microglial polarization is a subtle mechanism which maintains immunological homeostasis and has emerged as a putative therapeutic to combat AD. Berberine (BBR) is a natural alkaloid compound with multiple pharmacological effects, and has shown considerable therapeutic potential against inflammatory disorders. However, BBR functions and underlying mechanisms in neuroinflammation remain unclear.

Purpose: To examine BBR pharmacological effects and mechanisms in neuroinflammation with a view to treating AD.

Methods: BBR effects on cognitive performance in 5 × FAD mice were assessed using open field, Y-maze, and Morris Water Maze (MWM) tests. Neuroinflammation-related markers and Aβ pathology were examined in brain sections from mice. Transcriptomic analyses of hippocampus tissues were also conducted. Microglial BV2 cells were also used to verify potential BBR mechanisms in neuroinflammation and microglial polarization.

Results: BBR improved cognitive performance, reduced amyloid pathology, and alleviated aberrant neuroinflammation in an AD mouse model. BBR induced microglial polarization to an M2-like phenotype, which was manifested by lowered and elevated proinflammatory and anti-inflammatory cytokine production, respectively, improved microglial uptake and Aβ clearance. Mechanistically, BBR directly interacted with TYROBP and promoted its activation by stabilizing TYROBP oligomerization. TYROBP knockdown aggravated M1-like polarization and pro-inflammatory gene expression in microglial cells in the presence of lipopolysaccharide (LPS)+Aβ, while blocked microglial M2-like polarization benefited from BBR administration.

Conclusions: BBR modulated neuroinflammation by regulating microglial polarization via TYROBP activation. Our study provided new insight into BBR pharmacological actions in regulating microglial homeostasis and combating AD.