13 Mar 2024

Last year, scientists led by Tony Wyss-Coray, Stanford University, reported that Aβ induced formation of lipid droplets within human microglia, and attributed this to an uptick in a triglyceride synthesis enzyme. APOE4 aggravated lipid droplet formation, and APOE4/4 carriers who had had Alzheimer’s disease had many fat-filled microglia in their brain tissue. E4/4 glia poisoned neurons, suggesting that the cells release something neurotoxic, perhaps the lipids themselves.

This work was published in Nature on March 13. Alzforum covered it as a preprint (Sep 2023 news).

Fatal Fat? When microglia sense Aβ, they upregulate ASCL1. This causes droplets of triglycerides to form, more so in APOE4/4 glia than in E3/3 cells. The former releases neurotoxic substances. [Courtesy of Haney et al., Nature, 2024.]

In brief, co-first authors Michael Haney, who is now at the University of Pennsylvania in Philadelphia, and Róbert Pálovics treated human induced pluripotent stem-cell-derived microglia from APOE3/3 and APOE4/4 carriers with synthetic Aβ42 fibrils. A day later, only the APOE4/4 cells filled with triglyceride droplets.

The scientists pegged the lipid accumulation to overexpression of long-chain fatty acyl-CoA synthetase 1. ACSL1 is an enzyme in the triglyceride synthesis pathway; it pins CoA onto free fatty acids.

In cortical tissue from people who’d had AD, ACSL1-expressing and droplet-filled microglia surrounded amyloid plaques. ACSL1 rose in step with droplets, and was the most upregulated microglial gene in AD cases.

APOE played a role, too. APOE4/4 AD tissue had abundant lipid-filled microglia that cranked out ACSL1, while E3/3 tissue had fewer such microglia and lower expression.

Fat-filled APOE4/4 microglia seemed fatal to neurons, releasing something toxic. Human iPSC-derived neurons immersed in media from E4/4 microglia cultures overproduced the apoptosis protein caspase, AT8-positive phospho-tau, and triglyceride droplets. Haney suspects the neurotoxic substances exuded by microglia might be the triglycerides themselves, and plans to identify them in his new lab at UPenn.—Chelsea Weidman Burke

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References

News Citations

1. Lipid-Laden, Sluggish Microglia? Blame Aβ. 6 Sep 2023

Further Reading

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