Multi-omics reveals changes in astrocyte fatty acid metabolism during early stages of Alzheimer's disease

Background Astrocytes undergo extensive changes during Alzheimer's disease (AD), including reactive transformations induced by Aβ deposition and adjustments in lipid metabolism, ion balance, neuronal support, and inflammatory responses. Although dysfunctional astrocytes are known to contribute to AD progression, a detailed characterization of the dynamic alterations in astrocytes at the levels of transcriptome, proteome and metabolome during the progression of AD, especially in its early stages, is lacking. Methods We conducted an integrated multi-omics profiling of astrocytes obtained from APPswe/PSEN1ΔE9 transgenic AD and WT mice, including transcriptomics, proteomics, spatial metabolomics, to characterize the dynamic changes in astrocyte profiles over the course of AD progression. To investigate whether similar changes are present in early human AD and related to disease outcomes, we also analyzed single-nucleus RNA sequencing data of human brain samples, and dietary profiles and cognitive function data in human subjects to establish the link between astrocyte phenotypes and AD progression. Results Multi-omics profiling revealed significant changes in fatty acid metabolism of astrocytes in 6-month-old AD mice, especially deficiency in synthesis of unsaturated fatty acids. Such dysregulation in fatty acid metabolism was also observed in astrocytes from human brain samples with low AD pathology. Analysis of human dietary profiles demonstrated significant associations between dietary composition of polyunsaturated and saturated fatty acids and cognitive function. Conclusion Our study identified abnormal fatty acid metabolism as a hallmark of astrocytes at early stages of AD before the onset of apparent symptoms, revealing a close link between dysregulated fatty acid metabolism and disease progression.