Characterizing the metabolomes of microglia, astrocytes, and neurons in the brain across states of health, aging, and disease

Neurons and glia are distinct in their morphology, development, and function. They have unique transcriptomes and proteomes, but little is known about their metabolomes. The challenge of brain cell metabolic profiling is to obtain a large number of pure cells for reliable analysis. Here, we purify microglia, astrocytes, and neurons from the genetically labeled-brain. We identified >70 metabolites in them with targeted metabolomics and 9,854 metabolite features with untargeted metabolomics. We systematically characterized cell type–enriched metabolites and metabolic pathways. The enrichment of glutathione (GSH) metabolism in microglia was further validated in vivo. A significant decrease in GSH levels and GSH metabolism observed in microglia in aging and Alzheimer's disease (AD) models. Disrupting GSH metabolism in microglia results in aberrant morphogenesis, upregulation of mitophagy-related genes, and the deposition of β-Amyloid. Our results provide a valuable resource for metabolic studies related to aging, AD and other neurological diseases.