Neurochemistry international · 2025
Multi-omics reveals changes in astrocyte fatty acid metabolism during early stages of Alzheimer's disease.
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Zhong Jie, Li Manhui, Dai Ziwei, Wan Jun
Аннотация
BACKGROUND: Although astrocytes are known to contribute to Alzheimer's disease (AD) progression, their dynamic molecular alterations remain poorly characterized, particularly in early stages of the disease.
METHODS: We performed multi-omics profiling (transcriptomics, proteomics, spatial metabolomics) of astrocytes from APP/PS1 and WT mice to characterize dynamic changes during AD progression. To assess similar changes in early human AD, we analyzed single-nucleus RNA sequencing data from human samples.
RESULTS: Transcriptomic analysis of astrocytes from APP/PS1 and WT mice at five time points (2, 4, 6, 9, and 12 months of age) showed notable gene expression differences at 6 months, with reduced activity in fatty acid metabolism pathways (e.g., PPAR signaling, biosynthesis of unsaturated fatty acids). An astrocyte-specific metabolic model confirmed these disruptions. Proteomic analysis corroborated this by showing decreased activity in pathways like butanoate metabolism and PPAR signaling. Spatial metabolomics of brain slices from APP/PS1 and WT mice highlighted fatty acid enrichment in the hippocampus and cortex, alongside differential metabolites specific to the AD mouse model. Single-cell RNA sequencing analysis of human brain samples further showed fatty acid metabolism abnormalities in astrocytes from early AD cases versus controls, emphasizing its role in AD progression.
CONCLUSION: Our study identified abnormal fatty acid metabolism as an early feature of astrocytes in AD, suggesting an association between dysregulated fatty acid metabolism and disease progression.
METHODS: We performed multi-omics profiling (transcriptomics, proteomics, spatial metabolomics) of astrocytes from APP/PS1 and WT mice to characterize dynamic changes during AD progression. To assess similar changes in early human AD, we analyzed single-nucleus RNA sequencing data from human samples.
RESULTS: Transcriptomic analysis of astrocytes from APP/PS1 and WT mice at five time points (2, 4, 6, 9, and 12 months of age) showed notable gene expression differences at 6 months, with reduced activity in fatty acid metabolism pathways (e.g., PPAR signaling, biosynthesis of unsaturated fatty acids). An astrocyte-specific metabolic model confirmed these disruptions. Proteomic analysis corroborated this by showing decreased activity in pathways like butanoate metabolism and PPAR signaling. Spatial metabolomics of brain slices from APP/PS1 and WT mice highlighted fatty acid enrichment in the hippocampus and cortex, alongside differential metabolites specific to the AD mouse model. Single-cell RNA sequencing analysis of human brain samples further showed fatty acid metabolism abnormalities in astrocytes from early AD cases versus controls, emphasizing its role in AD progression.
CONCLUSION: Our study identified abnormal fatty acid metabolism as an early feature of astrocytes in AD, suggesting an association between dysregulated fatty acid metabolism and disease progression.