Leptin reduces Alzheimer's disease-related tau phosphorylation in neuronal cells.
Leptin is a centrally acting hormone controlling metabolic pathways. Recently, it was shown that leptin can reduce amyloid beta levels both in vitro and in vivo. Herein, phosphorylation of tau was investigated following treatment of neuronal cells with leptin and insulin. Specifically, phosphorylation of tau at amino acid residues Ser(202), Ser(396) and Ser(404) was monitored in retinoic acid induced, human cell lines: SH-SY5Y and NTera-2. Both hormones induced a concentration- and time-dependent reduction of tau phosphorylation, and were synergistic at suboptimum concentrations. Importantly, leptin was 300-fold more potent than insulin (IC(50)L=46.9 nM vs. IC(50)I=13.8 microM). A central role for AMP-dependent kinase as a mediator of leptin's action is demonstrated by the ability of 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) to decrease tau phosphorylation, and by blocking leptin in the presence of Compound C. Thus, leptin, which ameliorates both amyloid beta and tau-related pathological pathways, holds promise as a novel therapeutic for Alzheimer's disease.
Greco
Steven J
SJ
Neurotez Inc., Bridgewater, NJ, USA.
Sarkar
Sraboni
S
Johnston
Jane M
JM
Zhu
Xiongwei
X
Su
Bo
B
Casadesus
Gemma
G
Ashford
J Wesson
JW
Smith
Mark A
MA
Tezapsidis
Nikolaos
N
D055372:AMP-Activated Protein Kinases; D000544:Alzheimer Disease / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism*
D007328:Insulin; D020738:Leptin; D009097:Multienzyme Complexes; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; D016875:tau Proteins; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
Biochem Biophys Res Commun. 2006 Dec 8;351(1):171-5
17054914
Cell. 2006 Sep 8;126(5):955-68
16959574
Eur J Neurosci. 2007 Dec;26(12):3429-36
18052981
J Biol Chem. 2008 Jan 4;283(1):100-9
17971449
J Neurosci Res. 2008 Jul;86(9):2091-9
18335524
Neurobiol Aging. 2009 Sep;30(9):1483-9
18358569
J Neurochem. 2008 Sep;106(5):1977-90
18466320
Nature. 2000 Apr 6;404(6778):661-71
10766253
J Biol Chem. 2000 Aug 11;275(32):24977-83
10818091
Dement Geriatr Cogn Disord. 2001 Mar-Apr;12(2):167-70
11173891
Nature. 2002 Jan 17;415(6869):339-43
11797013
Ann N Y Acad Sci. 2002 Jun;967:379-88
12079865
Trends Pharmacol Sci. 2002 Jun;23(6):288-93
12084635
Neuron. 2003 Jul 31;39(3):409-21
12895417
Nature. 2004 Apr 1;428(6982):569-74
15058305
Biochem Biophys Res Commun. 2004 Jul 2;319(3):993-1000
15184080
Dev Biol. 1984 Jun;103(2):285-93
6144603
J Biol Chem. 1997 Aug 1;272(31):19547-53
9235959
J Neurochem. 1999 Feb;72(2):576-84
9930729
Nature. 1999 Sep 2;401(6748):73-6
10485707
FASEB J. 2004 Dec;18(15):1870-8
15576490
J Neurosci. 2007 Dec 12;27(50):13635-48
18077675