Blocking Fat Storage Enzyme Quiets Alzheimer's-Linked Brain Immune Cells

Neuroinflammation is a core driver of Alzheimer's disease (AD) progression, and microglia — the CNS's resident immune cells — are central mediators. A long-standing open question has been whether the lipid droplet accumulation consistently observed in activated microglia is functionally necessary or merely a byproduct of immune activation. This study, from a multi-institute NIH team, provides a direct causal answer.

The researchers used human induced pluripotent stem cell (iPSC)-derived microglia from multiple genetic backgrounds and differentiation protocols. They showed that both extrinsic activation via lipopolysaccharide (LPS) and the intrinsic Alzheimer's risk factor APOE4 genotype independently drive accumulation of triglyceride-rich lipid droplets. Raman imaging microscopy confirmed increases in total lipids, triglycerides, cholesterol esters, and phospholipids following LPS treatment, mirroring transcriptional upregulation of lipid synthesis genes and downregulation of lipid catabolism genes.

To test causality, the team inhibited DGAT1 and DGAT2 — the two enzymes catalyzing the rate-limiting step of triglyceride biosynthesis — using selective pharmacological inhibitors and shRNA-mediated knockdown. DGAT inhibition blocked lipid droplet formation and, strikingly, suppressed LPS-induced inflammatory cytokine and chemokine transcription and secretion. Transcriptomic analysis identified four gene clusters differentially affected by LPS with or without DGAT inhibition; the largest cluster (223 genes) contained immune activation genes upregulated by LPS but blunted by DGAT inhibition, encompassing cytokines, NF-κB targets, and lipid metabolism genes. Conversely, inhibiting lipid catabolism via ATGL (the lipid droplet lipase) also impaired the inflammatory response, demonstrating that both synthesis and breakdown of triglycerides are required for full microglial immune activation.

In microglia carrying the APOE4 genotype — generated from isogenic iPSC lines differing only at the APOE locus — DGAT inhibition attenuated APOE4-associated disease transcriptional signatures and partially normalized aberrant phagocytosis. Most functionally, DGAT inhibition rescued microglial surveillance defects observed in ex vivo brain slices from APOE4 humanized transgenic mice, demonstrating relevance in a tissue context.

These findings reframe lipid droplet accumulation from a passive correlate of microglial activation to an active metabolic requirement. By establishing that triglyceride biosynthesis is necessary for both extrinsically- and intrinsically-driven microglial immune states, the study identifies DGAT1/2 inhibition as a potential therapeutic strategy for dampening neuroinflammation in Alzheimer's disease.