Abstract
Disruption of leptin signalling has been implicated as playing a role in the development of Alzheimer’s disease (AD). Leptin has previously been shown to be affected by amyloid-beta (Aβ)-related signalling; however, pathways that link leptin to the disease pathogenesis have not been determined. To characterize the association between increasing age-dependent Aβ levels with leptin signalling and the vulnerable brain regions in AD, we assessed the mRNA and protein expression profile of leptin and leptin receptor (Ob-Rb) at 9 and 18-month-age in APP/PS1 mice. Immunohistochemical labelling demonstrated that leptin and Ob-Rb proteins were localised to neocortical and hippocampal neurons in APP/PS1 and wildtype (WT) mice. Neuronal leptin and Ob-Rb immunolabelling was more prominent in the neocortex of both groups at 9 month of age, while, at 18 months, labelling was reduced in the hippocampus of APP/PS1 mice relative to WT. Immunoblotting analysis demonstrated decreased hippocampal leptin levels, concomitantly with an increased Ob-Rb levels, in APP/PS1 mice compared with WT controls at 18 month of age. While no leptin mRNA was found in either of the groups analysed, Ob-Rb mRNA was significantly decreased in the hippocampus of APP/PS1 mice at both ages analysed. In addition, a significant decreased protein kinase B (Akt) activity concomitantly with an upregulation of suppressor of cytokine signaling-3 (SOCS3) and protein-tyrosine phosphatase 1B (PTP1B) transcripts was present. Thus, these results collectively indicate alterations of leptin signalling in the hippocampus of APP/PS1 mice, providing novel insights about the pathways that could link aberrant leptin signaling to the pathological changes of AD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arendash GW, King DL, Gordon MN, Morgan D, Hatcher JM, Hope CE, Diamond DM (2001) Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res 891:42–53
Bonda DJ, Stone JG, Torres SL, Siedlak SL, Perry G, Kryscio R, Jicha G, Casadesus G, Smith MA, Zhu X, Lee HG (2014) Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance. J Neurochem 128:162–172. https://doi.org/10.1111/jnc.12380
Chakrabarti S, Khemka VK, Banerjee A, Chatterjee G, Ganguly A, Biswas A (2015) Metabolic risk factors of sporadic Alzheimer's disease: implications in the pathology, pathogenesis and treatment. Aging Dis 6:282–299. https://doi.org/10.14336/AD.2014.002ad-6-4-282
Farr SA, Banks WA, Morley JE (2006) Effects of leptin on memory processing. Peptides 27:1420–1425. https://doi.org/10.1016/j.peptides.2005.10.006
Fernandez CM et al (2009) The expression of rat resistin isoforms is differentially regulated in visceral adipose tissues: effects of aging and food restriction. Metabolism 58:204–211
Fernandez-Galaz MC, Fernandez-Agullo T, Carrascosa JM, Ros M, Garcia-Segura LM (2010) Leptin accumulation in hypothalamic and dorsal raphe neurons is inversely correlated with brain serotonin content. Brain Res 1329:194–202. https://doi.org/10.1016/j.brainres.2010.02.085
Fernandez-Martos CM (2017) Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer’s disease. Alzheimers Dement: Transl Res Clin Interv 3:92–106
Fernandez-Martos CM, Gonzalez-Fernandez C, Gonzalez P, Maqueda A, Arenas E, Rodriguez FJ (2011) Differential expression of Wnts after spinal cord contusion injury in adult rats. PLoS One 6:e27000. https://doi.org/10.1371/journal.pone.0027000PONE-D-11-06684
Fernandez-Martos CM, King AE, Atkinson RA, Woodhouse A, Vickers JC (2015) Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer's disease. Neurobiol Aging 36:2757–2767. https://doi.org/10.1016/j.neurobiolaging.2015.07.003S0197-4580(15)00359-0
Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N (2004) Obesity-related leptin regulates. Alzheimer's Abeta FASEB J 18:1870–1878. https://doi.org/10.1096/fj.04-2572com
Folch J, Patraca I, Martínez N, Pedrós I, Petrov D, Ettcheto M, Abad S, Marin M, Beas-Zarate C, Camins A (2015) The role of leptin in the sporadic form of Alzheimer's disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin. Life Sci 140:19–28. https://doi.org/10.1016/j.lfs.2015.05.002S0024-3205(15)00258-1
Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770. https://doi.org/10.1038/27376
Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24:516–524. https://doi.org/10.1016/j.nbd.2006.08.017
Garza JC, Guo M, Zhang W, Lu XY (2008) Leptin increases adult hippocampal neurogenesis in vivo and in vitro. J Biol Chem 283:18238–18247. https://doi.org/10.1074/jbc.M800053200M800053200
Gonzalez-Fernandez C, Fernandez-Martos CM, Shields SD, Arenas E, Javier Rodriguez F (2014) Wnts are expressed in the spinal cord of adult mice and are differentially induced after injury. J Neurotrauma 31:565–581. https://doi.org/10.1089/neu.2013.3067
Greco SJ, Sarkar S, Johnston JM, Zhu X, Su B, Casadesus G, Ashford JW, Smith MA, Tezapsidis N (2008) Leptin reduces Alzheimer's disease-related tau phosphorylation in neuronal cells. Biochem Biophys Res Commun 376:536–541
Greco SJ, Sarkar S, Casadesus G, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N (2009a) Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells. Neurosci Lett 455:191–194
Greco SJ, Sarkar S, Johnston JM, Tezapsidis N (2009b) Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun 380:98–104
Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N, Casadesus G (2010) Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 19:1155–1167. https://doi.org/10.3233/JAD-2010-1308
Harvey J (2007) Leptin: a diverse regulator of neuronal function. J Neurochem 100:307–313
Harvey J, Solovyova N, Irving A (2006) Leptin and its role in hippocampal synaptic plasticity. Prog Lipid Res 45:369–378. https://doi.org/10.1016/j.plipres.2006.03.001
Hikita M, Bujo H, Hirayama S, Takahashi K, Morisaki N, Saito Y (2000) Differential regulation of leptin receptor expression by insulin and leptin in neuroblastoma cells. Biochem Biophys Res Commun 271:703–709. https://doi.org/10.1006/bbrc.2000.2692S0006-291X(00)92692-5
Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O'Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100
Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D (1999) Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet 29:177–185
Holden KF, Lindquist K, Tylavsky FA, Rosano C, Harris TB, Yaffe K (2009) Serum leptin level and cognition in the elderly: findings from the health ABC study. Neurobiol Aging 30:1483–1489. https://doi.org/10.1016/j.neurobiolaging.2007.11.024S0197-4580(07)00454-X
Horvath TL, Sarman B, Garcia-Caceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Bronneke HS, Levin BE, Diano S, Cowley MA, Tschop MH (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci U S A 107:14875–14880. https://doi.org/10.1073/pnas.1004282107
Hyman BT, Damasio H, Damasio AR, Van Hoesen GW (1989) Alzheimer's disease. Annu Rev Public Health 10:115–140. https://doi.org/10.1146/annurev.pu.10.050189.000555
Ishii M (2016) The role of the adipocyte hormone leptin in Alzheimer's disease. Keio J Med 65:21. https://doi.org/10.2302/kjm.65-002-ABST
Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170. https://doi.org/10.1093/hmg/ddh019
Jastroch M, Morin S, Tschop MH, Yi CX (2014) The hypothalamic neural-glial network and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab 28:661–671. https://doi.org/10.1016/j.beem.2014.02.002
Kamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs JA, Jansen AHP, Verveer M, de Groot LR, Smith VD, Rangarajan S, Rodríguez JJ, Orre M, Hol EM (2012) GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One 7:e42823. https://doi.org/10.1371/journal.pone.0042823PONE-D-12-13276
Koh SH, Baek W, Kim SH (2011) Brief review of the role of glycogen synthase kinase-3beta in amyotrophic lateral sclerosis. Neurol Res Int 2011:205761. https://doi.org/10.1155/2011/205761
Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S (2009) Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA 302:2565–2572. https://doi.org/10.1001/jama.2009.1836302/23/2565
Liu Y, Staal JA, Canty AJ, Kirkcaldie MTK, King AE, Bibari O, Mitew ST, Dickson TC, Vickers JC (2013) Cytoskeletal changes during development and aging in the cortex of neurofilament light protein knockout mice. J Comp Neurol 521:1817–1827. https://doi.org/10.1002/cne.23261
Liu Y, Atkinson RA, Fernandez-Martos CM, Kirkcaldie MT, Cui H, Vickers JC, King AE (2015) Changes in TDP-43 expression in development, aging, and in the neurofilament light protein knockout mouse. Neurobiol Aging 36:1151–1159. https://doi.org/10.1016/j.neurobiolaging.2014.10.001S0197-4580(14)00637-X
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)). Method Methods 25:402–408
Maioli S, Lodeiro M, Merino-Serrais P, Falahati F, Khan W, Puerta E, Codita A, Rimondini R, Ramirez MJ, Simmons A, Gil-Bea F, Westman E, Cedazo-Minguez A, the Alzheimer's Disease Neuroimaging Initiative (2015) Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease. Aging Cell 14:122–129. https://doi.org/10.1111/acel.12281
Mitchell SE, Nogueiras R, Morris A, Tovar S, Grant C, Cruickshank M, Rayner DV, Dieguez C, Williams LM (2009) Leptin receptor gene expression and number in the brain are regulated by leptin level and nutritional status. J Physiol 587:3573–3585. https://doi.org/10.1113/jphysiol.2009.173328jphysiol.2009.173328
Morrison CD, White CL, Wang Z, Lee SY, Lawrence DS, Cefalu WT, Zhang ZY, Gettys TW (2007) Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. Endocrinology 148:433–440. https://doi.org/10.1210/en.2006-0672
Moult PR, Milojkovic B, Harvey J (2009) Leptin reverses long-term potentiation at hippocampal CA1 synapses. J Neurochem 108:685–696. https://doi.org/10.1111/j.1471-4159.2008.05810.xJNC5810
Niedowicz DM, Studzinski CM, Weidner AM, Platt TL, Kingry KN, Beckett TL, Bruce-Keller AJ, Keller JN, Murphy MP (2013) Leptin regulates amyloid beta production via the gamma-secretase complex. Biochim Biophys Acta 1832:439–444. https://doi.org/10.1016/j.bbadis.2012.12.009S0925-4439(12)00300-6
Pedros I et al (2014) Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease. Biochim Biophys Acta 1842:1556–1566. https://doi.org/10.1016/j.bbadis.2014.05.025
Peralta S, Carrascosa JM, Gallardo N, Ros M, Arribas C (2002) Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction. Biochem Biophys Res Commun 296:425–428
Perez-Gonzalez R et al (2014) Leptin gene therapy attenuates neuronal damages evoked by amyloid-beta and rescues memory deficits in APP/PS1 mice. Gene Ther 21:298–308. https://doi.org/10.1038/gt.2013.85gt201385
Petrov D et al (2015) High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents. Biochim Biophys Acta 1852:1687–1699. https://doi.org/10.1016/j.bbadis.2015.05.004S0925-4439(15)00147-7
Power DA, Noel J, Collins R, O'Neill D (2001) Circulating leptin levels and weight loss in Alzheimer's disease patients. Dement Geriatr Cogn Disord 12:167–170
Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, Leibel RL (1996) Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab 81:3424–3427. https://doi.org/10.1210/jcem.81.9.8784109
Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T (2011) Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging 32:1626–1633. https://doi.org/10.1016/j.neurobiolaging.2009.10.009S0197-4580(09)00339-X
Scarpace PJ, Matheny M, Shek EW (2000) Impaired leptin signal transduction with age-related obesity. Neuropharmacology 39:1872–1879
Searcy JL, Phelps JT, Pancani T, Kadish I, Popovic J, Anderson KL, Beckett TL, Murphy MP, Chen KC, Blalock EM, Landfield PW, Porter NM, Thibault O (2012) Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease. J Alzheimers Dis 30:943–961. https://doi.org/10.3233/JAD-2012-11166107T40865VP760877
Stephens TW, Basinski M (1995) The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377:530–532
Stuart KE, King AE, Fernandez-Martos CM, Dittmann J, Summers MJ, Vickers JC (2017) Mid-life environmental enrichment increases synaptic density in CA1 in a mouse model of Abeta-associated pathology and positively influences synaptic and cognitive health in healthy ageing. J Comp Neurol 525:1797–1810. https://doi.org/10.1002/cne.24156
Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S (2009) Leptin: a novel therapeutic strategy for Alzheimer's disease. J Alzheimers Dis 16:731–740. https://doi.org/10.3233/JAD-2009-10213375752606620632
Valladolid-Acebes I, Fole A, Martin M, Morales L, Cano MV, Ruiz-Gayo M, Del Olmo N (2013) Spatial memory impairment and changes in hippocampal morphology are triggered by high-fat diets in adolescent mice. Is there a role of leptin? Neurobiol Learn Mem 106:18–25. https://doi.org/10.1016/j.nlm.2013.06.012S1074-7427(13)00104-4
Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL, Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group (2013) Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 12:357–367. https://doi.org/10.1016/S1474-4422(13)70044-9S1474-4422(13)70044-9
Wan J, Fu AKY, Ip FCF, Ng HK, Hugon J, Page G, Wang JH, Lai KO, Wu Z, Ip NY (2010) Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer's disease. J Neurosci 30:6873–6881. https://doi.org/10.1523/JNEUROSCI.0519-10.201030/20/6873
Watson GS, Craft S (2003) The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs 17:27–45
Wilkinson M, Morash B, Ur E (2000) The brain is a source of leptin. Front Horm Res 26:106–125
Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG (2002) PTP1B regulates leptin signal transduction in vivo. Dev Cell 2:489–495
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432
Acknowledgements
The authors would like to gratefully acknowledge Graeme McCormack for his excellent technical support. The authors declare that they have no conflict of interest. This work was supported by the funding from J.O. and J.R. Wicking Trust (Equity Trustees).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Suppl. Fig.1
IHC negative controls. (A-H) Representative images processed without the primary antibodies, leptin and Ob-Rb, as controls, in both WT (A-G) and APP/PS1 (B-H) sections at 9 month of age. No non-specific staining was observed in any of the immunohistochemical controls. Images were collected on an Axio lab A.1 microscope and AxioCam ICc5 camera (both Zeiss, Germany), with ×5, ×20 and ×40 objectives. Scale bars = 20 μm. Black square indicates the hippocampal region of interest magnified with the ×40 objective. Abbreviations: CTX, neocortex; HP, hippocampus. (JPEG 2521 kb)
Rights and permissions
About this article
Cite this article
King, A., Brain, A., Hanson, K. et al. Disruption of leptin signalling in a mouse model of Alzheimer’s disease. Metab Brain Dis 33, 1097–1110 (2018). https://doi.org/10.1007/s11011-018-0203-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-018-0203-9