Aβ oligomers promote lipid droplet accumulation and inflammatory responses in astrocytes but not neurons.

Lipid droplets (LDs) are dynamic organelles central to cellular lipid homeostasis. Emerging evidence implicates LDs in Alzheimer's disease (AD) pathogenesis, though their cell-type-specific roles remain poorly defined. Here, we investigated the effects of amyloid-beta oligomers (AβOs) on LDs accumulation, oxidative stress, and inflammatory activation in primary astrocytes and neurons. We found that AβOs selectively triggered robust LDs formation in astrocytes, accompanied by significant increases in triglyceride (TG) and cholesterol (TC) content, and upregulation of the LD-associated protein perilipin 2 (PLIN2). Furthermore, AβOs induced pronounced oxidative stress, evidenced by elevated Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and promoted inflammatory activation via increased secretion of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) in astrocytes. By contrast, neurons showed no significant changes in lipid metabolism, oxidative stress, or inflammatory responses under identical treatment conditions. Our results underscore the central role of astrocytes in AβO-induced metabolic and inflammatory dysregulation, revealing a cell-type-specific vulnerability with potential implications for AD pathogenesis. These in vitro findings provide a mechanistic basis for lipid-focused therapeutic strategies, pending further in vivo validation.