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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
Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease
Priya Prakash1, Palak Manchanda1, Evi Paouri2
1Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Abstract:
Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. Diacylglycerol O-acyltransferase 2 (DGAT2)-a key enzyme that converts FFAs to TGs-promoted microglial LD formation and was increased in mouse 5xFAD and human AD brains. Pharmacologically targeting DGAT2 improved microglial uptake of Aβ and reduced plaque load and neuronal damage in 5xFAD mice. These findings identify a lipid-mediated mechanism underlying microglial dysfunction that could become a therapeutic target for AD.
Insights
Microglia form lipid droplets (LDs) when exposed to amyloid-beta (Aβ), impairing their function in Alzheimer's disease (AD). Targeting the enzyme DGAT2 reduces LDs, enhancing Aβ clearance and protecting against AD pathology.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Genetic studies link microglial phagocytosis genes to Alzheimer's disease (AD) risk.
- The cellular mechanisms underlying microglial dysfunction in AD remain unclear.
Purpose of the Study:
- To investigate the role of lipid metabolism in microglial dysfunction in AD.
- To identify potential therapeutic targets for AD based on microglial lipid metabolism.
Main Methods:
- Examined microglial lipid droplet (LD) formation upon amyloid-beta (Aβ) exposure in vitro and in AD models.
- Performed lipidomic analyses to identify metabolic changes in microglia.
- Investigated the role of Diacylglycerol O-acyltransferase 2 (DGAT2) in microglial LD formation and AD pathology.
- Pharmacologically inhibited DGAT2 in 5xFAD mice and assessed Aβ phagocytosis, plaque load, and neuronal damage.
Main Results:
- Microglia exposed to Aβ formed LDs, with increased LD loads near amyloid plaques in AD brains and 5xFAD mice.
- LD-laden microglia showed impaired Aβ phagocytosis.
- Lipidomic analysis revealed a shift towards triacylglycerol (TG) synthesis and decreased free fatty acids (FFAs) during LD formation.
- DGAT2, an enzyme converting FFAs to TGs, promoted microglial LD formation and was upregulated in AD models.
- DGAT2 inhibition improved microglial Aβ uptake and reduced neuropathology in 5xFAD mice.
Conclusions:
- Microglial LD formation, driven by DGAT2-mediated lipid metabolism, contributes to Aβ phagocytosis defects in AD.
- Targeting DGAT2 represents a potential therapeutic strategy to restore microglial function and mitigate AD progression.
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