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Updated: Jul 26, 2025
Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease
Priya Prakash1, Palak Manchanda1, Evi Paouri2
1Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Abstract:
Several microglia-expressed genes have emerged as top risk variants for Alzheimer's disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aβ), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent on age and disease progression and is prominent in the hippocampus in mice and humans. Despite differences in microglial LD load between brain regions and sexes in mice, LD-laden microglia exhibited a deficit in Aβ phagocytosis. Unbiased lipidomic analysis identified a decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. DGAT2, a key enzyme for converting FFAs to TGs, promotes microglial LD formation and is increased in 5xFAD and human AD brains. Inhibition or degradation of DGAT2 improved microglial uptake of Aβ and drastically reduced plaque load in 5xFAD mice, respectively. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.
Insights
Alzheimer's disease risk genes impair microglia by promoting lipid droplet formation, hindering amyloid-beta clearance. Targeting DGAT2 enzyme improves microglial function and reduces amyloid plaques, offering a new therapeutic avenue.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Microglia-expressed genes are linked to Alzheimer's disease (AD) risk.
- Impaired microglial phagocytosis is a proposed mechanism for neurodegeneration in AD.
- The precise mechanisms linking AD-risk genes to microglial dysfunction are unknown.
Purpose of the Study:
- To investigate the role of lipid metabolism in microglial dysfunction in Alzheimer's disease.
- To identify the molecular mechanisms by which AD-risk genes affect microglial function.
- To explore DGAT2 as a potential therapeutic target for AD.
Main Methods:
- Microglial lipid droplet formation was assessed upon amyloid-beta exposure in AD mouse models and human brains.
- Lipidomic analysis was performed to identify metabolic changes.
- DGAT2 enzyme activity was modulated (inhibition/degradation) to evaluate its impact on microglial function and AD pathology.
Main Results:
- Microglia form lipid droplets upon amyloid-beta exposure, with increased load near plaques in AD models and human brains.
- Lipid droplet formation is associated with decreased free fatty acids and increased triacylglycerols, mediated by DGAT2.
- LD-laden microglia show impaired amyloid-beta phagocytosis.
- DGAT2 inhibition or degradation improved phagocytosis and reduced amyloid plaque burden in AD mice.
Conclusions:
- Lipid droplet accumulation, driven by DGAT2, is a novel mechanism of microglial dysfunction in Alzheimer's disease.
- Targeting DGAT2 can restore microglial phagocytic function and ameliorate AD pathology.
- This study identifies a new lipid-mediated pathway as a potential therapeutic target for Alzheimer's disease.
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