Metabolic Astrocytic Support with Decanoic Acid Enhances Energy Metabolism in Alzheimer's Disease Models.

Alzheimer's disease (AD) is increasingly recognized as a disorder of cerebral energy metabolism, where impaired glucose utilization contributes to disease pathology. Medium-chain fatty acids (MCFAs), such as decanoic acid (C10), have emerged as promising metabolic substrates due to their ability to bypass glycolytic deficits and support mitochondrial function. In this study, we investigated the metabolic impact of C10 in the 5xFAD mouse model of AD and in human induced pluripotent stem cell (hiPSC)-derived astrocytes carrying familial AD mutations. Utilizing stable (13)C-labeled metabolic tracers, we demonstrated that while [U-(13)C]glucose metabolism was largely preserved in cortical slices of 6-month-old 5xFAD female mice, [1,2-(13)C]acetate uptake was significantly reduced, suggesting impaired astrocytic metabolism. [U-(13)C]C10 was efficiently metabolized in both WT and 5xFAD brain slices, particularly in astrocytes, as indicated by high labeling of glutamine and citrate. Furthermore, C10 competitively inhibited glucose and acetate metabolism, suggesting its potential as an auxiliary energy substrate. In hiPSC-derived astrocytes, AD-specific metabolic responses to C10 varied by mutation, with only partial alterations in oxidative glucose metabolism observed in APP and PSEN1 variants, highlighting genotype-dependent metabolic alterations. While AD-related mutations in the hiPSC models did not lead to robust deficits, the in vivo environment in the 5xFAD model is associated with measurable metabolic changes in astrocytes. These findings underscore astrocytic metabolic dysfunction in AD and suggest that C10 supplementation may restore brain energy by supporting astrocytic oxidative metabolism.