Stephenson RA, Sepulveda J, Johnson KR, Lita A, Gopalakrishnan J, Acri DJ, Beilina A, Cheng L, Yang LG, Root JT, Ward ME, Combs C, Skarnes WC, Cookson MR, Shih HY, Larion M, Rebeck GW, Narayan PS. Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4. Cell Rep. 2025 Jul 22;44(7):115961. Epub 2025 Jul 10 PubMed.
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University of Pennsylvania
University of Pennsylvania
This is a very exciting study. Stephenson et al. rigorously demonstrate that triglyceride (TG) lipid droplets (LDs) play a critical role in the production of damaging cytokines, such as TNF-α and IL1β, in iPSC-derived microglia. The authors do this using multiple iPSC lines and differentiation methods, as well as through both pharmacological and genetic perturbation of DGAT and ACSL1 enzymes. This work further validates many recent studies in mouse models of AD indicating that amyloid induces TG lipid droplets in microglia and that decreasing microglial TG LDs reduces AD pathology in mouse models (Prakash et al., 2025; Wu et al., 2025). Similar to previous reports (Haney et al., 2024), they find that the transcriptional effect of inflammation-induced TG synthesis in iMG is regulated by NF-κB, and importantly, the authors show TG reduction inhibits NF-κB nuclear translocation.
Stephenson et al. further demonstrate these LD phenotypes are related to the APOE4 genotype by showing elevated LDs in isogenic APOE4 induced MG, confirming previous findings that associated APOE4 with TG filled LDs (Victor et al., 2022; Liu et al., 2023; Haney et al. 2024; Friday et al., 2025) and highlighting a cell-autonomous role of the APOE4 genotype in microglia. Importantly, they show that lowering TGs in APOE4 microglia through DGAT inhibition rescues APOE4-related defects in motility in mouse brain slices. These findings give further support to microglial triglyceride lipid droplet accumulation as an important new drug target in AD, a target strongly supported by human genetics but for which there is no therapeutic.
One somewhat paradoxical finding was that inhibition of ATGL, a lipase essential for the catabolism of TGs from LDs, had similar effects on cytokine release and phagocytosis as DGAT inhibition. This would suggest that both LD biosynthesis and catabolism may be necessary for microglial activation in response to LPS. This raises the question of what is the mechanistic link between TG catabolism and microglial response to LPS? This is also very exciting in the context of recent findings that APOE is a lipid droplet-associated protein and that APOE variants modify LD formation and size (Windham et al., 2024). In future studies, it may be interesting to investigate this TG catabolism finding further in the context of the APOE4 genotype, or in animal models, to determine if this is exclusive to LPS stimulation or is a broader aspect of microglial activation in neurodegeneration.
References:
Prakash P, Manchanda P, Paouri E, Bisht K, Sharma K, Rajpoot J, Wendt V, Hossain A, Wijewardhane PR, Randolph CE, Chen Y, Stanko S, Gasmi N, Gjojdeshi A, Card S, Fine J, Jethava KP, Clark MG, Dong B, Ma S, Crockett A, Thayer EA, Nicolas M, Davis R, Hardikar D, Allende D, Prayson RA, Zhang C, Davalos D, Chopra G. Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease. Immunity. 2025 Jun 10;58(6):1536-1552.e8. Epub 2025 May 19 PubMed.
Wu X, Miller JA, Lee BT, Wang Y, Ruedl C. Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer's disease mouse model. Sci Adv. 2025 Feb 7;11(6):eadq6038. Epub 2025 Feb 5 PubMed.
Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JC, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, Wyss-Coray T. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia. Nature. 2024 Apr;628(8006):154-161. Epub 2024 Mar 13 PubMed.
Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, Samaan G, Murdock MH, von Maydell D, Effenberger AH, Cerit O, Wen HL, Liu L, Welch G, Bonner M, Tsai LH. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8. PubMed.
Liu CC, Wang N, Chen Y, Inoue Y, Shue F, Ren Y, Wang M, Qiao W, Ikezu TC, Li Z, Zhao J, Martens Y, Doss SV, Rosenberg CL, Jeevaratnam S, Jia L, Raulin AC, Qi F, Zhu Y, Alnobani A, Knight J, Chen Y, Linares C, Kurti A, Fryer JD, Zhang B, Wu LJ, Kim BY, Bu G. Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease. Nat Immunol. 2023 Nov;24(11):1854-1866. Epub 2023 Oct 19 PubMed.
Friday CM, Stephens IO, Smith CT, Lee S, Satish D, Devanney NA, Cohen S, Morganti JM, Gordon SM, Johnson LA. APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses. Neurobiol Dis. 2025 Aug;212:106983. Epub 2025 May 30 PubMed.
Windham IA, Powers AE, Ragusa JV, Wallace ED, Zanellati MC, Williams VH, Wagner CH, White KK, Cohen S. APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size. J Cell Biol. 2024 Apr 1;223(4) Epub 2024 Feb 9 PubMed.
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