Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells.
Leptin, which serves as a lipid-modulating hormone to control metabolic energy availability, is decreased in Alzheimer's disease (AD) patients, and serum levels are inversely correlated to severity of dementia. We have previously described the effects of leptin in reducing amyloid beta protein both in vitro and in vivo, and tau phosphorylation in vitro. Herein, we systematically investigated the signaling pathways activated by leptin, leading to these molecular endpoints, to better understand its mechanism of action. Inhibition of amyloid beta production and tau phosphorylation in leptin-treated human and/or rat neuronal cultures were both dependent on activation of AMP-activated protein kinase (AMPK). Direct stimulation of AMPK with the cell-permeable activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), replicated leptin's effects and conversely, Compound C, an inhibitor of AMPK, blocked leptin's action. The data implicate that AMPK is a key regulator of both AD-related pathways.
Greco
Steven J
SJ
Neurotez, Inc., Research and Development, 991 Highway 22, Suite 200A, Bridgewater, NJ 08807, USA.
Sarkar
Sraboni
S
Johnston
Jane M
JM
Tezapsidis
Nikolaos
N
D000091162:AMP-Activated Protein Kinase Kinases; D000544:Alzheimer Disease / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D020738:Leptin; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; D016875:tau Proteins; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide