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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Microglia-derived Galectin-9 drives amyloid-β pathology in Alzheimer's disease
Guoxin Zhang1, Qinyu Peng1, Xiaodi Guo1
1Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Abstract:
The accumulation of amyloid-β (Aβ) and overactivation of microglia contribute to the pathogenesis of Alzheimer's disease (AD), but the interaction between microglial activation and Aβ deposition in AD remains elusive. Here we revealed that Aβ activates microglia and promotes the release of Galectin-9 (Gal-9), a member of the β-galactoside-binding family of lectins. The levels of Gal-9 in the cerebrospinal fluid and brain tissues of AD patients are higher than those in control subjects. Gal-9 interacts with Aβ and promotes its aggregation, generating Gal-9-Aβ fibrils with enhanced seeding activity and neurotoxicity. The expression of Gal-9 increases with age in the brains of APP/PS1 transgenic mice. Knockout of Gal-9 in APP/PS1 mice substantially reduced Aβ sedimentation, neuroinflammation, and cognitive impairment. Moreover, depletion of Gal-9 inhibited the seeding activity of brain homogenates from APP/PS1 mice. These findings reveal a mechanism by which microglia-derived Gal-9 accelerates Aβ aggregation and seeding in AD. Thus, strategies aimed at inhibiting Gal-9 may hold promise as a disease-modifying therapy to alleviate AD pathology.
Insights
Alzheimer's disease involves amyloid-β (Aβ) and microglia. This study shows Galectin-9 (Gal-9) released by microglia accelerates Aβ aggregation and neurotoxicity, suggesting Gal-9 inhibition as a potential therapy.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-β (Aβ) accumulation and microglial activation.
- The interplay between microglial activation and Aβ deposition in AD is not fully understood.
Purpose of the Study:
- To elucidate the role of microglia-derived Galectin-9 (Gal-9) in Alzheimer's disease pathology.
- To investigate the interaction between Gal-9 and Aβ in AD progression.
Main Methods:
- Assessed Gal-9 levels in cerebrospinal fluid and brain tissues of AD patients and controls.
- Investigated Gal-9's effect on Aβ aggregation and neurotoxicity in vitro.
- Examined Gal-9 expression in APP/PS1 transgenic mice.
- Utilized Gal-9 knockout APP/PS1 mice to evaluate its in vivo impact on Aβ pathology, neuroinflammation, and cognitive function.
Main Results:
- Aβ activates microglia, leading to increased Gal-9 release.
- Elevated Gal-9 levels were observed in AD patients' cerebrospinal fluid and brain tissues.
- Gal-9 promotes Aβ aggregation, forming toxic Gal-9-Aβ fibrils with enhanced seeding activity.
- Gal-9 knockout in APP/PS1 mice significantly reduced Aβ deposition, neuroinflammation, and cognitive deficits, and inhibited brain homogenate seeding activity.
Conclusions:
- Microglia-derived Galectin-9 plays a critical role in accelerating Aβ aggregation and seeding in Alzheimer's disease.
- Inhibiting Gal-9 presents a promising therapeutic strategy for mitigating AD pathology.
