β-Amyloid regulates leptin expression and tau phosphorylation through the mTORC1 signaling pathway

P>High levels of the adipocytokine leptin are associated with reduced risk of Alzheimer's disease. Leptin treatment also reduces beta-amyloid (A beta) levels in in vivo and in vitro models of Alzheimer's disease. A beta and leptin interact with the Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Akt/mTORC1 activation reduces tau phosphorylation through the inhibition of the downstream enzyme GSK-3 beta. mTORC1 also regulates translation of many proteins including leptin. While A beta has been shown to inactivate Akt, inhibit mTORC1, and facilitate the phosphorylation of tau, leptin activates both Akt and mTORC1 and reduces tau phosphorylation. However, the extent to which A beta may modulate leptin expression and increase tau phosphorylation involving Akt/mTORC1 has not been determined. In this study, we show that incubation of organotypic slices from rabbit hippocampus with A beta down-regulates leptin expression, inhibits Akt, activates GSK-3 beta, increases tau phosphorylation, and inactivates mTORC1. Leptin treatment reverses A beta effects by alleviating Akt inhibition, preventing GSK-3 beta activation, reducing tau phosphorylation, and activating mTORC1. On the other hand, Rapamycin, an allosteric inhibitor of mTORC1, down-regulates leptin expression, increases tau phosphorylation, and does not affect Akt and GSK-3 beta. Our results demonstrate for the first time that A beta regulates leptin expression and tau phosphorylation through mTORC1.