Leptin Regulates Tau Phosphorylation and Amyloid Through AMPK in Neuronal Cells

Overview

Journal Biochem Biophys Res Commun

Publisher Elsevier

Specialty Biochemistry

Date 2009 Jan 27

PMID 19166821

Citations 87

Authors

Steven J Greco

Sraboni Sarkar

Jane M Johnston

Nikolaos Tezapsidis

Affiliations

Soon will be listed here.

Abstract

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.

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References

Greco S, Sarkar S, Johnston J, Zhu X, Su B, Casadesus G . Leptin reduces Alzheimer's disease-related tau phosphorylation in neuronal cells. Biochem Biophys Res Commun. 2008; 376(3):536-41. PMC: 2577167. DOI: 10.1016/j.bbrc.2008.09.026. View

Guillozet A, Weintraub S, Mash D, Marsel Mesulam M . Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol. 2003; 60(5):729-36. DOI: 10.1001/archneur.60.5.729. View

Hu Y, Qiao L, Wang S, Rong S, Meuillet E, Berggren M . 3-(Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, Akt, and cancer cell growth. J Med Chem. 2000; 43(16):3045-51. DOI: 10.1021/jm000117y. View

Park S, Jang J, Jun D, Hong S . Exercise enhances insulin and leptin signaling in the cerebral cortex and hypothalamus during dexamethasone-induced stress in diabetic rats. Neuroendocrinology. 2006; 82(5-6):282-93. DOI: 10.1159/000093127. View

de Laszlo S, Visco D, Agarwal L, Chang L, Chin J, Croft G . Pyrroles and other heterocycles as inhibitors of p38 kinase. Bioorg Med Chem Lett. 1999; 8(19):2689-94. DOI: 10.1016/s0960-894x(98)00495-8. View

Rossner S, Sastre M, Bourne K, Lichtenthaler S . Transcriptional and translational regulation of BACE1 expression--implications for Alzheimer's disease. Prog Neurobiol. 2006; 79(2):95-111. DOI: 10.1016/j.pneurobio.2006.06.001. View

Thornton T, Pedraza-Alva G, Deng B, Wood C, Aronshtam A, Clements J . Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science. 2008; 320(5876):667-70. PMC: 2597039. DOI: 10.1126/science.1156037. View

Semple R, Chatterjee V, ORahilly S . PPAR gamma and human metabolic disease. J Clin Invest. 2006; 116(3):581-9. PMC: 1386124. DOI: 10.1172/JCI28003. View

Fewlass D, Noboa K, Pi-Sunyer F, Johnston J, Yan S, Tezapsidis N . Obesity-related leptin regulates Alzheimer's Abeta. FASEB J. 2004; 18(15):1870-8. DOI: 10.1096/fj.04-2572com. View

10.

Gustafson D . Adiposity indices and dementia. Lancet Neurol. 2006; 5(8):713-20. DOI: 10.1016/S1474-4422(06)70526-9. View

11.

McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K . Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999; 46(6):860-6. DOI: 10.1002/1531-8249(199912)46:6<860::aid-ana8>3.0.co;2-m. View

12.

Whitmer R, Gunderson E, Barrett-Connor E, Quesenberry Jr C, Yaffe K . Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ. 2005; 330(7504):1360. PMC: 558283. DOI: 10.1136/bmj.38446.466238.E0. View

13.

Jamsa A, Hasslund K, Cowburn R, Backstrom A, Vasange M . The retinoic acid and brain-derived neurotrophic factor differentiated SH-SY5Y cell line as a model for Alzheimer's disease-like tau phosphorylation. Biochem Biophys Res Commun. 2004; 319(3):993-1000. DOI: 10.1016/j.bbrc.2004.05.075. View

14.

Wang J, Grundke-Iqbal I, Iqbal K . Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci. 2007; 25(1):59-68. PMC: 3191918. DOI: 10.1111/j.1460-9568.2006.05226.x. View

15.

Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K . Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A. 2001; 98(12):6923-8. PMC: 34454. DOI: 10.1073/pnas.121119298. View

16.

Ramamurthy S, Ronnett G . Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain. J Physiol. 2006; 574(Pt 1):85-93. PMC: 1817796. DOI: 10.1113/jphysiol.2006.110122. View

17.

Hanihara T, Amano N, Takahashi T, Nagatomo H, Yagashita S . Distribution of tangles and threads in the cerebral cortex in progressive supranuclear palsy. Neuropathol Appl Neurobiol. 1995; 21(4):319-26. DOI: 10.1111/j.1365-2990.1995.tb01066.x. View

18.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

19.

King T, Song L, Jope R . AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3. Biochem Pharmacol. 2006; 71(11):1637-47. PMC: 1618797. DOI: 10.1016/j.bcp.2006.03.005. View

20.

Hooper C, Killick R, Lovestone S . The GSK3 hypothesis of Alzheimer's disease. J Neurochem. 2007; 104(6):1433-9. PMC: 3073119. DOI: 10.1111/j.1471-4159.2007.05194.x. View