Amino acid metabolic checkpoints in microglia: emerging regulators of Alzheimer’s disease pathogenesis
Year: 2026
Type: article
Abstract: 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.
Source: Frontiers in Aging Neuroscience
Authors: Fei Xu, Honglin Li, Miao Zhang
Institution: Heilongjiang University of Chinese Medicine
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225761962