Amino acid metabolic checkpoints in microglia: emerging regulators of Alzheimer’s disease pathogenesis

Microglial immunometabolic reprogramming is increasingly implicated in Alzheimer’s disease (AD), but amino acid metabolism has received less integrated attention than glucose and lipid metabolism. This Mini Review examines tryptophan-kynurenine, arginine, and glutamine pathways because they connect amino acid flux or amino acid-derived metabolites with microglial redox control, inflammatory signaling, mitochondrial function, and amyloid handling. We use the term amino acid metabolic checkpoints narrowly for a molecular regulatory node that has a demonstrable link to amino acid availability, transport, metabolic flux, or an amino acid-derived ligand and whose perturbation changes a defined microglial function. Broad domains such as mitochondrial fitness and phagolysosomal competence are treated as functional outputs rather than checkpoints. The glutamine-NLRP3 literature illustrates why directionality and experimental context are essential: glutaminase inhibition can promote mitophagy and suppress NLRP3 activation, whereas NLRP3 loss or chronic pharmacological inhibition increases glutamine/glutamate-related metabolism, mitochondrial activity, and Aβ clearance. These findings support bidirectional coupling rather than a simple model in which glutaminolysis is uniformly pathogenic. Evidence for tryptophan- and arginine-related nodes is biologically compelling but more heterogeneous in cell type and disease context. A checkpoint framework that explicitly grades direct versus indirect evidence may therefore help prioritize cell- and stage-specific immunometabolic intervention in AD.