Leptin rescues neurons from Alzheimer’s disease-related pathways triggered by lipid burden

Steven J. Greco, George Perry, J. Wesson Ashford, Ashkan Hamzelou, Jane M. Johnston, Nikolaos Tezapsidis

Neurotez, Inc., Bridgewater, USA.
Stanford/VA Medical Center, Palo Alto, USA.
University of Texas, San Antonio, USA.

DOI: 10.4236/aad.2013.21004                

Abstract

Adipocyte-derived leptin is a pleiotropic hormone implicated in control of lipid storage and mobilization, bone homeostasis, immune function and neuronal plasticity. Leptin has been shown to prevent accumulation of extracellular Aβ and hyperphosphorylation of tau in both cell culture and animal models. Herein an investigation was undertaken to test leptin’s ability to prevent the exacerbation/activation of AD-related pathways in neurons following their exposure to a high concentration of a variety of lipids. Specifically, cholesterol, oleic acid and/or ceramide were added to the media of cells resulting in decreased cellular viability and energy metabolism, and in increased tau phosphorylation and extracellular Aβ. Leptin increased viability, boosted cellular metabolism by activating AMP-activated protein kinase (AMPK) and the sirtuins (SIRT) and reduced tau phosphorylation and Aβ accumulation in a dose-dependent manner in response to select challenges. These findings demonstrate that leptin can attenuate the harmful effect of certain lipids that lead to exacerbation or activation of AD pathways. The study herein also provides the basis for a novel screening platform to define and identify a novel class of “metabolic” compounds addressing Alzheimer’s disease, based on a biological profile similar to leptin.

Keywords

Leptin; Cholesterol; Ceramide; AMPK; SIRT; Alzheimer’s; Tau; Amyloid-β

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Bhat, N.R. (2010) Linking cardiometabolic disorders to sporadic Alzheimer’s disease: A perspective on potential mechanisms and mediators. Journal of Neurochemistry 115, 551-562. doi:10.1111/j.1471-4159.2010.06978.x
[2]	Watson, G.S. and Craft, S. (2003) The role of insulin resistance in the pathogenesis of Alzheimer’s disease: Implications for treatment. CNS Drugs, 17, 27-45. doi:10.2165/00023210-200317010-00003
[3]	Hooijmans, C.R., Van der Zee, C.E., Dederen, P.J., Brouwer, K.M., Reijmer, Y.D., Van Groen, T., Broersen, L.M., Lutjohann, D., Heerschap, A. and Kiliaan, A.J. (2009) DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice. Neurobiology of Disease, 33, 482-498. doi:10.1016/j.nbd.2008.12.002
[4]	Moroz, N., Tong, M., Longato, L., Xu, H. and De la Monte, S.M. (2008) Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus. Journal of Alzheimer’s Disease: JAD, 15, 29-44.
[5]	Whitmer, R.A., Gunderson, E.P., Barrett-Connor, E., Quesenberry Jr., C.P. and Yaffe, K. (2005) Obesity in middle age and future risk of dementia: A 27-year longitudinal population based study. BMJ, 330, 1360. doi:10.1136/bmj.38446.466238.E0
[6]	Whitmer, R.A,, Gustafson, D.R., Barrett-Connor, E., Haan, M.N., Gunderson, E.P. and Yaffe, K. (2008) Central obesity and increased risk of dementia more than three decades later. Neurology, 71, 1057-1064. doi:10.1212/01.wnl.0000306313.89165.ef
[7]	Huang, X.F., Koutcherov, I., Lin, S., Wang, H.Q. and Storlien, L. (1996) Localization of leptin receptor mRNA expression in mouse brain. Neuroreport, 7, 2635-2638. doi:10.1097/00001756-199611040-00045
[8]	Harvey, J., Shanley, L.J., O’Malley, D. and Irving, A.J. (2005) Leptin: A potential cognitive enhancer? Biochemical Society Transactions, 33, 1029-1032. doi:10.1042/BST20051029
[9]	Dietrich, M.O., Spuch, C., Antequera, D., Rodal, I., De Yebenes, J.G., Molina, J.A., Bermejo, F. and Carro, E. (2008) Megalin mediates the transport of leptin across the blood-CSF barrier. Neurobiology of Aging, 29, 902-912. doi:10.1016/j.neurobiolaging.2007.01.008
[10]	Adam, C.L. and Findlay, P.A. (2010) Decreased bloodbrain leptin transfer in an ovine model of obesity and weight loss: Resolving the cause of leptin resistance. International Journal of Obesity, 34, 980-988. doi:10.1038/ijo.2010.28
[11]	Barrett-Connor, E., Edelstein, S.L., Corey-Bloom, J. and Wiederholt, W.C. (1996) Weight loss precedes dementia in community-dwelling older adults. Journal of American Geriatrics Society, 44, 1147-1152.
[12]	Mazzali, G., Bissoli, L., Gambina, S., Residori, L., Pagliari, P., Guariento, S., Sun, M., Broggio, E., Bosello, O. and Zamboni, M. (2002) Energy balance in Alzheimer’s disease. The Journal of Nutrition Health and Aging, 6, 247-253.
[13]	Olsson, T., Nasman, B., Rasmuson, S. and Ahren, B. (1998) Dual relation between leptin and cortisol in humans is disturbed in Alzheimer’s disease. Biological Psychiatry, 44, 374-376.
[14]	Power, D.A., Noel, J., Collins, R. and O’Neill, D. (2001) Circulating leptin levels and weight loss in Alzheimer’s disease patients. Dementia and Geriatric Cognitive Disorders, 12, 167-170. doi:10.1159/000051252
[15]	Zhou, R., Deng, J., Zhang, M., Zhou, H.D. and Wang, Y.J. (2011) Association between bone mineral density and the risk of Alzheimer’s disease. Journal of Alzheimer’s Disease: JAD, 24, 101-108.
[16]	Bigalke, B., Schreitmuller, B., Sopova, K., Paul, A., Stransky, E., Gawaz, M., Stellos, K. and Laske, C. (2011) Adipocytokines and CD34 progenitor cells in Alzheimer’s disease. PloS One, 6, e20286. doi:10.1371/journal.pone.0020286
[17]	Ray, S. and Wyss-Coray, A. (2005) Methods for diagnosis, stratification, and monitoring of Alzheimer’s disease. World Intellectual Property Organization, WO 2005/ 052592 A2, Satoris, Inc., Menlo Park.
[18]	Holden, K.F., Lindquist, K., Rosano, C., Tylavsky, F.A., Harris, T.B. and Yaffe, K. (2006) Low serum leptin is associated with poor cognitive performance in the elderly. 58th Annual Meeting of American Academy of Neurology, San Diego, 1-8 April 2006, p. S41.006.
[19]	Holden, K.F., Lindquist, K., Tylavsky, F.A., Rosano, C., Harris, T.B. and Yaffe, K. (2008) Serum leptin level and cognition in the elderly: Findings from the health ABC study. Neurobiology of Aging, 30, 1483-1489.
[20]	Lieb, W., Beiser, A.S., Vasan, R.S., Tan, Z.S., Au, R., Harris, T.B., Roubenoff, R., Auerbach, S., DeCarli, C., Wolf, P.A. and Seshadri, S. (2009) Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA: The Journal of the American Medical Association, 302, 2565-2572. doi:10.1001/jama.2009.1836
[21]	Puglielli, L., Tanzi, R.E. and Kovacs, D.M. (2003) Alzheimer’s disease: the cholesterol connection. Nature Neuroscience, 6, 345-351. doi:10.1038/nn0403-345
[22]	Glockner, F., Meske, V., Lutjohann, D. and Ohm, T.G. (2011) Dietary cholesterol and its effect on tau protein: a study in apolipoprotein Edeficient and P301L human tau mice. Journal of Neuropathology and Experimental Neurology, 70, 292-301. doi:10.1097/NEN.0b013e318212f185
[23]	Wilson, D.M. and Binder, L.I. (1997) Free fatty acids stimulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer’s disease. The American Journal of Pathology, 150, 2181-2195.
[24]	Hooff, G.P., Peters, I., Wood, W.G., Muller, W.E. and Eckert, G.P. (2010) Modulation of cholesterol, farnesylpyrophosphate, and geranylgeranylpyrophosphate in neuroblastoma SH-SY5Y-APP695 cells: Impact on amyoid beta-protein production. Molecular Neurobiology, 41, 341-350. doi:10.1007/s12035-010-8117-5
[25]	Darios, F., Muriel, M.P., Khondiker, M.E., Brice, A. and Ruberg, M. (2005) Neurotoxic calcium transfer from endoplasmic reticulum to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 25, 4159-4168.
[26]	Haughey, N.J., Bandaru, V.V., Bae, M. and Mattson, M.P. (2010) Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis. Biochimica et Biophysica Acta, 1801, 878-886. doi:10.1016/j.bbalip.2010.05.003
[27]	Liu, Y., Yang, L., Conde-Knape, K., Beher, D., Shearman, M.S. and Shachter, N.S. (2004) Fatty acids increase presenilin-1 levels and [gamma]-secretase activity in PSwt-1 cells. Journal of Lipid Research, 45, 2368-2376. doi:10.1194/jlr.M400317-JLR200
[28]	Merched, A., Xia, Y., Visvikis, S., Serot, J.M. and Siest, G. (2000) Decreased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer’s disease. Neurobiology of Aging, 21, 27-30. doi:10.1016/S0197-4580(99)00103-7
[29]	Mahley, R.W. and Huang, Y. (2006) Apolipoprotein (apo) E4 and Alzheimer’s disease: Unique conformational and biophysical properties of apoE4 can modulate neuropathology. Acta Neurologica Scandinavica. Supplementum, 185, 8-14. doi:10.1111/j.1600-0404.2006.00679.x
[30]	Fewlass, D.C., Noboa, K., Pi-Sunyer, F.X., Johnston, J.M., Yan, S.D. and Tezapsidis, N. (2004) Obesity-related leptin regulates Alzheimer’s Aβ. FASEB Journal, 18, 1870-1878. doi:10.1096/fj.04-2572com
[31]	Greco, S.J., Hamzelou, A., Johnston, J.M., Smith, M.A., Ashford, J.W. and Tezapsidis, N. (2011) Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and beta-amyloid in neurons. Biochemical and Biophysical Research Communications, 414, 170-174. doi:10.1016/j.bbrc.2011.09.050
[32]	Greco, S.J., Sarkar, S., Casadesus, G., Zhu, X., Smith, M.A., Ashford, J.W., Johnston, J.M. and Tezapsidis, N. (2009) Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells. Neuroscience Letters, 455, 191-194. doi:10.1016/j.neulet.2009.03.066
[33]	Greco, S.J., Sarkar, S., Johnston, J.M. and Tezapsidis, N. (2009) Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochemical and Biophysical Research Communications, 380, 98-104. doi:10.1016/j.bbrc.2009.01.041
[34]	Greco, S.J., Bryan, K.J., Sarkar, S., Zhu, X., Smith, M.A., Ashford, J.W., Johnston, J.M., Tezapsidis, N. and Casadesus, G. (2010) Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer’s disease. Journal of Alzheimer’s Disease: JAD, 19, 1155-1167.
[35]	Greco, S.J., Sarkar, S., Johnston, J.M., Zhu, X., Su, B., Casadesus, G., Ashford, J.W., Smith, M.A. and Tezapsidis, N. (2008) Leptin reduces Alzheimer’s disease-related tau phosphorylation in neuronal cells. Biochemical and Biophysical Research Communications, 376, 536-541. doi:10.1016/j.bbrc.2008.09.026
[36]	Wang, Y., Nishi, M., Doi, A., Shono, T., Furukawa, Y., Shimada, T., Furuta, H., Sasaki, H. and Nanjo, K. (2010) Ghrelin inhibits insulin secretion through the AMPK-UCP2 pathway in beta cells. FEBS Letters, 584, 1503-1508. doi:10.1016/j.febslet.2010.02.069
[37]	Yeh, C.H., Chen, T.P., Wang, Y.C., Lin, Y.M. and Fang, S.W. (2010) AMP-activated protein kinase activation during cardioplegia-induced hypoxia/reoxygenation injury attenuates cardiomyocytic apoptosis via reduction of endoplasmic reticulum stress. Mediators of Inflammation, 2010, 130636. doi:10.1155/2010/130636
[38]	Martins, I.C., Kuperstein, I., Wilkinson, H., Maes, E., Vanbrabant, M., Jonckheere, W., Van Gelder, P., Hartmann, D., D’Hooge, R., De Strooper, B., Schymkowitz, J. and Rousseau, F. (2008) Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice. The EMBO Journal, 27, 224-233. doi:10.1038/sj.emboj.7601953
[39]	Kapogiannis, D. and Mattson, M.P. (2011) Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurology, 10, 187-198. doi:10.1016/S1474-4422(10)70277-5
[40]	Pasinetti, G.M. and Eberstein, J.A. (2008) Metabolic syndrome and the role of dietary lifestyles in Alzheimer’s disease. Journal of Neurochemistry, 106, 1503-1514. doi:10.1111/j.1471-4159.2008.05454.x
[41]	Leduc, V., Jasmin-Belanger, S. and Poirier, J. (2010) APOE and cholesterol homeostasis in Alzheimer’s disease. Trends in Molecular Medicine, 16, 469-477. doi:10.1016/j.molmed.2010.07.008
[42]	Fraser, T., Tayler, H. and Love, S. (2010) Fatty acid composition of frontal, temporal and parietal neocortex in the normal human brain and in Alzheimer's disease. Neurochemical Research, 35, 503-513. doi:10.1007/s11064-009-0087-5
[43]	Foley, P. (2010) Lipids in Alzheimer’s disease: A century-old story. Biochimica et Bio-physica Acta, 1801, 750-753.