Octodon degus as a naturally polymorphic model to study ApoE-associated lipid dysregulation in Alzheimer’s Disease

Classic rodent models for Alzheimer's Disease (AD) mainly rely on transgenic mice overexpressing mutant human genes to mimic rare familial AD, but often fail to reproduce the diversity of its signs and symptoms, raising construct and face validity concerns. Octodon degus instead develop AD-like pathology spontaneously with age, combining a long lifespan, diurnal habits, and naturally occurring ApoE variants (Tan et al., 2022; Hurley et al., 2018; Mugnaini et al., 2022), the strongest genetic risk factor for AD in humans, where isoform-specific effects otherwise require artificially humanized mouse models. We examined whether ApoE variation at position 213 affects cellular lipid homeostasis, comparing two prevalent variants, E and K, representing wild-type-like and risk-associated states. In primary fibroblasts from genotyped animals, ApoE213K cells showed increased lipid droplet number and size versus ApoE213E cells, mirroring APOE4-linked lipid droplet dysfunction in human AD. In human astrocytes engineered to express the degu ApoE213 variants, untargeted proteomic and lipidomic profiling revealed widespread dysregulation of lipid-related proteins and lipids, converging on increased lipid biosynthesis and reduced lipid export, a "lipid trap" phenotype that may underlie the fibroblast lipid droplet phenotype. These findings contribute to establishing Octodon degus as a powerful natural model linking ApoE variation, lipid biology, and Alzheimer's disease risk.