Natalia Álvarez-Roger
Jayvon Nougaisse
Xin-Yun Lu

Universidad Central del Caribe School of Medicine, Bayamón, Puerto Rico
Augusta University, Department of Neuroscience, Georgia, United States of America

Introduction

Progressive neurodegeneration and cognitive decline are hallmarks of Alzheimer’s disease (AD), the world’s leading cause of dementia. The most potent genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4), which worsens amyloid-β aggregation and disrupts lipid metabolism. The main source of ApoE4 is astrocytes, which are important for lipid metabolism in the central nervous system. ApoE4 astrocytes also accumulate lipid droplets to a greater degree than ApoE3 astrocytes. Lipid droplet (LD) metabolism is controlled by the neuroprotective transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ). Previous work has shown that PPAR-γ activation reduces LDs in activated microglia. The goal of this study was to determine whether PPAR-γ also regulates LD formation in ApoE4-expressing astrocytes. We hypothesize that PPAR-γ activation mitigates LD accumulation in ApoE4 astrocytes.

Methods

To test this hypothesis, Rosiglitazone, a selective PPAR-γ agonist (50 µM), and DMSO, the vehicle control, were administered to ApoE4-expressing astrocytes for a duration of 4 hours. A neutral lipid dye was used to visualize and quantify LDs, and the proportion of cells exhibiting LD production was examined using flow cytometry.

Results

Preliminary results show that Rosiglitazone-treated ApoE4 astrocytes exhibited a tendency towards reduced LD number and intensity than vehicle-treated ApoE4 astrocytes. After PPAR-γ activation, flow cytometry demonstrated a decrease in the proportion of astrocytes that were LD-positive. These results suggest that PPAR-γ could play a role in lowering ApoE4 astrocyte lipid buildup.

Conclusion

Rosiglitazone-induced PPAR-γ activation may be a therapeutic option to address abnormalities in lipid metabolism in ApoE4-expressing astrocytes, which are a major contributor to Alzheimer’s disease pathogenesis. More research is required to clarify the molecular pathways involved and to confirm these results using in vivo mice models.

Acknowledgments

This project was supported by the PARIS Summer Research Program at Augusta University and conducted under the mentorship of Dr. Xin-Yun Lu and Jayvon Nougaisse.

Keywords

Alzheimer’s Disease, Apolipoprotein E4 (ApoE4), Lipid Droplets (LDs), PPAR-γ Activation