Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells.
We have previously demonstrated that Leptin reduces extracellular amyloid beta (Abeta) protein both in vitro and in vivo, and intracellular tau phosphorylation in vitro. Further, we have shown that these effects are dependent on activation of AMP-activated protein kinase (AMPK) in vitro. Herein, we investigated downstream effectors of AMPK signaling directly linked to tau phosphorylation. One such target, of relevance to Alzheimer's disease (AD), may be GSK-3beta, which has been shown to be inactivated by Leptin. We therefore dissected the role of GSK-3beta in mediating Leptin's ability to reduce tau phosphorylation in neuronal cells. Our data suggest that Leptin regulates tau phosphorylation through a pathway involving both AMPK and GSK-3beta. This was based on the following: Leptin and the cell-permeable AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), reduced tau phosphorylation at AD-relevant sites similarly to the GSK-3beta inhibitor, lithium chloride (LiCl). Further, this reduction of tau phosphorylation was mimicked by the downregulation of GSK-3beta, achieved using siRNA technology and antagonized by the ectopic overexpression of GSK-3beta. These studies provide further insight into Leptin's mechanism of action in suppressing AD-related pathways.
Research & Development, Neurotez, Inc., Bridgewater, NJ 08807, USA.
Steven J
SJ
Greco
Sraboni
S
Sarkar
Gemma
G
Casadesus
Xiongwei
X
Zhu
Mark A
MA
Smith
J Wesson
JW
Ashford
Jane M
JM
Johnston
Nikolaos
N
Tezapsidis
D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*
D018692:Antimanic Agents; D007004:Hypoglycemic Agents; D020738:Leptin; D012265:Ribonucleotides; D016875:tau Proteins; D000620:Aminoimidazole Carboxamide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D018021:Lithium Chloride