APA
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Prakash*, P., Manchanda*, P., Paouri, E., Bisht, K., Sharma, K., Wijewardhane, P. R., … Chopra, G. (2023). Amyloid β induces lipid droplet-mediated microglial dysfunction in Alzheimer’s disease. BioRxiv.
Chicago/Turabian
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Prakash*, Priya, Palak Manchanda*, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Prageeth R. Wijewardhane, Caitlin E. Randolph, et al. “Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer’s Disease.” bioRxiv (2023).
MLA
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Prakash*, Priya, et al. “Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer’s Disease.” BioRxiv, 2023.
BibTeX Click to copy
@article{priya2023a,
title = {Amyloid β induces lipid droplet-mediated microglial dysfunction in Alzheimer’s disease},
year = {2023},
journal = {bioRxiv},
author = {Prakash*, Priya and Manchanda*, Palak and Paouri, Evi and Bisht, Kanchan and Sharma, Kaushik and Wijewardhane, Prageeth R. and Randolph, Caitlin E. and Clark, Matthew G. and Fine, Jonathan A and Thayer, Elizabeth A. and Crockett, Alexis and Gasmi, Nadia and Stanko, Sarah and Prayson, Richard and Zhang, Chi and Davalos, Dimitrios and Chopra, Gaurav}
}
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 upon age and disease progression and is more prominent in the hippocampus in mice and humans. Despite variability in LD load between microglia from male versus female animals and between cells from different brain regions, LD-laden microglia exhibited a deficit in Aβ phagocytosis. Unbiased lipidomic analysis identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation. We demonstrate that DGAT2, a key enzyme for the conversion of FFAs to TAGs, promotes microglial LD formation, is increased in microglia from 5xFAD and human AD brains, and that inhibiting DGAT2 improved microglial uptake of Aβ. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.