AMPKa2 Signals Amino Acid Insufficiency to Inhibit Protein Synthesis_Metabolomics raw data of human blood samples

The functional difference between the two catalytic subunits, a1 and a2, of AMPK complexes remains elusive. Herein, we report that AMPKa2 specifically transduces amino acid insufficiencysignalsto protein synthesis. Low amino acidlevels, high proteinlevels, and reduced AMPKa threonine 172 phosphorylation (p-T172) are observed in blood samples in patients with Alzherimer’s Disease (AD) from a cohortof 1,000,000 Chinese individuals. Loss of a2, but not a1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acids-activated general controlled non-repressed 2 (GCN2) specifically phosphorylates a2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. a2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and AICAR, as well as BCAA or protein restriction a2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKa2 as a specific amino acidabundance detector for protein synthesis.