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Published on: January 30, 2014
Berberine modulates microglial polarization by activating TYROBP in Alzheimer's disease
Yu Yang1, Jiwen Wu1, Luping Jia1
1Shandong Key Laboratory of Psychiatric and Behavioral Medicine, School of Mental Health, Jining Medical University, Jining, 272013, Shandong, China; Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Jining Medical University, Jining, 272013, Shandong, China.
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.
Insights
Berberine (BBR) improves Alzheimer's disease (AD) symptoms by reducing neuroinflammation and Aβ pathology. It achieves this by promoting beneficial microglial polarization through TYROBP activation, offering a potential therapeutic avenue.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid plaques and neuroinflammation.
- Microglial polarization is a key regulator of brain homeostasis and a potential therapeutic target for AD.
- Berberine (BBR), a natural alkaloid, shows anti-inflammatory potential, but its mechanisms in neuroinflammation and AD are unclear.
Purpose of the Study:
- To investigate the pharmacological effects and underlying mechanisms of Berberine (BBR) in neuroinflammation relevant to Alzheimer's disease (AD).
- To assess BBR's impact on cognitive function, Aβ pathology, and neuroinflammation in a mouse model of AD.
Main Methods:
- Cognitive performance was evaluated in 5 × FAD mice using behavioral tests (open field, Y-maze, Morris Water Maze).
- Neuroinflammation markers and Aβ pathology were analyzed in mouse brain tissues.
- Transcriptomic analysis and in vitro studies with microglial BV2 cells were performed to elucidate BBR's mechanisms.
Main Results:
- BBR treatment improved cognitive function, reduced Aβ burden, and alleviated neuroinflammation in AD mice.
- BBR induced a shift in microglial polarization towards an M2-like phenotype, enhancing Aβ clearance.
- Mechanistically, BBR activated TYROBP by stabilizing its oligomerization, which is crucial for its beneficial effects on microglial polarization.
Conclusions:
- Berberine (BBR) effectively modulates neuroinflammation in Alzheimer's disease (AD) by regulating microglial polarization.
- TYROBP activation is a key mechanism through which BBR exerts its neuroprotective effects.
- This study provides novel insights into BBR's therapeutic potential for AD by targeting microglial homeostasis.
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