β-Amyloid regulates leptin expression and tau phosphorylation through the mTORC1 signaling pathway.
High levels of the adipocytokine leptin are associated with reduced risk of Alzheimer's disease. Leptin treatment also reduces β-amyloid (Aβ) levels in in vivo and in vitro models of Alzheimer's disease. Aβ 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-3β. mTORC1 also regulates translation of many proteins including leptin. While Aβ 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 Aβ 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 Aβ down-regulates leptin expression, inhibits Akt, activates GSK-3β, increases tau phosphorylation, and inactivates mTORC1. Leptin treatment reverses Aβ effects by alleviating Akt inhibition, preventing GSK-3β 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-3β. Our results demonstrate for the first time that Aβ regulates leptin expression and tau phosphorylation through mTORC1.
Marwarha
Gurdeep
G
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA.
Dasari
Bhanu
B
Prabhakara
Jaya Prasanthi Rantham
JP
Schommer
Jared
J
Ghribi
Othman
O
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020738:Leptin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D020738:Leptin; D010446:Peptide Fragments; D054411:Receptors, Leptin; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus