Leucine Modulation of the mTOR Pathway for Cognition Modulation: Kinetic and In Vitro Studies and Model Development.

摘要

Leucine, an essential branch-chained amino acid (AA), has been shown to activate the mammalian target of rapamycin (mTOR) pathway to increase protein synthesis, and with methods for increasing brain levels, may be associated with enhanced cognitive memory formation in the brain. The current report describes studies of leucine kinetics in male Long-Evans rats, together with in vitro studies of the effects of leucine on the mTOR pathway and a mathematical model of the mTOR signaling pathway. We found that leucine was eliminated quickly from the blood after iv dosing (5 and 12.9 mg/kg), and levels in the brain were higher than blood, indicating active transport of leucine across the blood brain barrier (BBB). Altered brain levels of 17 other AAs suggest that the spike in leucine levels due to the iv injection tends to cause an increased brain influx of all AAs, but that competition for the L1 transporter mitigates this effect somewhat for many of the AAs that primarily make use of this system to enter the brain. In vitro studies using neuronal cells indicated that a single dose of leucine could not activate the mTOR pathway in a predictable manner, as indicated by increased levels of pS6K1, possibly due to incomplete translocation of the mTORC1 complex to the lysosomal membrane. Finally, in order to develop a mechanistic understanding of the impact of leucine and other amino acids on protein synthesis and neuronal plasticity, we implemented and modified a mathematical model of the mTOR signaling pathway.