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The Adiponectin Homolog Osmotin Enhances Neurite Outgrowth and Synaptic Complexity via AdipoR1/NgR1 Signaling in Alzheimer’s Disease

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Abstract

Alzheimer’s disease is a major neurodegenerative disease characterized by memory loss and cognitive deficits. Recently, we reported that osmotin, which is a homolog of adiponectin, improved long-term potentiation and cognitive functions in Alzheimer’s disease mice. Several lines of evidence have suggested that Nogo-A and the Nogo-66 receptor 1 (NgR1), which form a complex that inhibits long-term potentiation and cognitive function, might be associated with the adiponectin receptor 1 (AdipoR1), which is a receptor for osmotin. Here, we explore whether osmotin’s effects on long-term potentiation and memory function are associated with NgR1 signaling via AdipoR1 in Alzheimer’s disease. Osmotin reduced the expression of NgR1 without affecting Nogo-A expression. Furthermore, osmotin inhibited NgR1 signaling by prohibiting the formation of the Nogo-A and NgR1 ligand-receptor complex, resulting in enhanced neurite outgrowth; these effects disappeared in the presence of AdipoR1 interference. In addition, osmotin increased the expression of the pre- and postsynaptic markers synaptophysin and PSD-95, as well as the activation of the memory-associated markers AMPA receptor and CREB; these effects occurred in an AdipoR1- and NgR1-dependent manner. Osmotin was also found to enhance dendritic complexity and spine density in the hippocampal region of Alzheimer’s disease mouse brains. These results suggest that osmotin can enhance neurite outgrowth and synaptic complexity through AdipoR1 and NgR1 signaling, implying that osmotin might be an effective therapeutic agent for Alzheimer’s disease and that AdipoR1 might be a crucial therapeutic target for neurodegenerative diseases such as Alzheimer’s.

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References

  1. Katzman R (1986) Alzheimer’s disease. N Engl J Med 314(15):964–973. https://doi.org/10.1056/NEJM198604103141506

    Article  PubMed  CAS  Google Scholar 

  2. Cras P, Kawai M, Lowery D, Gonzalez-DeWhitt P, Greenberg B, Perry G (1991) Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proc Natl Acad Sci U S A 88(17):7552–7556. https://doi.org/10.1073/pnas.88.17.7552

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Brion JP (1998) Neurofibrillary tangles and Alzheimer’s disease. Eur Neurol 40(3):130–140. https://doi.org/10.1159/000007969

    Article  PubMed  CAS  Google Scholar 

  4. Larson EB, Kukull WA, Katzman RL (1992) Cognitive impairment: dementia and Alzheimer’s disease. Annu Rev Public Health 13(1):431–449. https://doi.org/10.1146/annurev.pu.13.050192.002243

    Article  PubMed  CAS  Google Scholar 

  5. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185. https://doi.org/10.1126/science.1566067

    Article  PubMed  CAS  Google Scholar 

  6. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R et al (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):311–321. https://doi.org/10.1056/NEJMoa1312889

    Article  PubMed  CAS  Google Scholar 

  7. Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403(6768):434–439. https://doi.org/10.1038/35000219

    Article  PubMed  CAS  Google Scholar 

  8. Huber AB, Schwab ME (2000) Nogo-A, a potent inhibitor of neurite outgrowth and regeneration. Biol Chem 381(5–6):407–419. https://doi.org/10.1515/BC.2000.053

    Article  PubMed  CAS  Google Scholar 

  9. Masliah E, Xie F, Dayan S, Rockenstein E, Mante M, Adame A, Patrick CM, Chan AF et al (2010) Genetic deletion of Nogo/Rtn4 ameliorates behavioral and neuropathological outcomes in amyloid precursor protein transgenic mice. Neuroscience 169(1):488–494. https://doi.org/10.1016/j.neuroscience.2010.04.045

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lee H, Raiker SJ, Venkatesh K, Geary R, Robak LA, Zhang Y, Yeh HH, Shrager P et al (2008) Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength. J Neurosci 28(11):2753–2765. https://doi.org/10.1523/JNEUROSCI.5586-07.2008

    Article  PubMed  CAS  Google Scholar 

  11. Karlen A, Karlsson TE, Mattsson A, Lundstromer K, Codeluppi S, Pham TM, Backman CM, Ogren SO et al (2009) Nogo receptor 1 regulates formation of lasting memories. Proc Natl Acad Sci U S A 106(48):20476–20481. https://doi.org/10.1073/pnas.0905390106

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ali T, Yoon GH, Shah SA, Lee HY, Kim MO (2015) Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. Sci Rep 5(1):11708. https://doi.org/10.1038/srep11708

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Shah SA, Yoon GH, Chung SS, Abid MN, Kim TH, Lee HY, Kim MO (2016) Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer’s disease neuropathological deficits. Mol Psychiatry 22(3):407–416. https://doi.org/10.1038/mp.2016.23

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Narasimhan ML, Coca MA, Jin J, Yamauchi T, Ito Y, Kadowaki T, Kim KK, Pardo JM et al (2005) Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeast through a homolog of mammalian adiponectin receptor. Mol Cell 17(2):171–180. https://doi.org/10.1016/j.molcel.2004.11.050

    Article  PubMed  CAS  Google Scholar 

  15. Yamauchi T, Kadowaki T (2008) Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes 32(Suppl 7):S13–S18. https://doi.org/10.1038/ijo.2008.233

    Article  CAS  Google Scholar 

  16. Wang X, Meng D, Chang Q, Pan J, Zhang Z, Chen G, Ke Z, Luo J et al (2010) Arsenic inhibits neurite outgrowth by inhibiting the LKB1-AMPK signaling pathway. Environ Health Perspect 118(5):627–634. https://doi.org/10.1289/ehp.0901510

    Article  PubMed  CAS  Google Scholar 

  17. Schmid RS, Pruitt WM, Maness PF (2000) A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis. J Neurosci 20(11):4177–4188

    Article  PubMed  CAS  Google Scholar 

  18. Miglio G, Rattazzi L, Rosa AC, Fantozzi R (2009) PPARgamma stimulation promotes neurite outgrowth in SH-SY5Y human neuroblastoma cells. Neurosci Lett 454(2):134–138. https://doi.org/10.1016/j.neulet.2009.03.014

    Article  PubMed  CAS  Google Scholar 

  19. Wang H, Shen J, Xiong N, Zhao H, Chen Y (2011) Protein kinase B is involved in Nogo-66 inhibiting neurite outgrowth in PC12 cells. Neuroreport 22(15):733–738. https://doi.org/10.1097/WNR.0b013e32834a58e8

    Article  PubMed  CAS  Google Scholar 

  20. Guo W, Qian L, Zhang J, Zhang W, Morrison A, Hayes P, Wilson S, Chen T et al (2011) Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling. J Neurosci Res 89(11):1723–1736. https://doi.org/10.1002/jnr.22725

    Article  PubMed  CAS  Google Scholar 

  21. Liu Y, Yao Z, Zhang L, Zhu H, Deng W, Qin C (2013) Insulin induces neurite outgrowth via SIRT1 in SH-SY5Y cells. Neuroscience 238:371–380. https://doi.org/10.1016/j.neuroscience.2013.01.034

    Article  PubMed  CAS  Google Scholar 

  22. Song J, Lee JE (2013) Adiponectin as a new paradigm for approaching Alzheimer’s disease. Anat Cell Biol 46(4):229–234. https://doi.org/10.5115/acb.2013.46.4.229

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ng RC, Cheng OY, Jian M, Kwan JS, Ho PW, Cheng KK, Yeung PK, Zhou LL et al (2016) Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice. Mol Neurodegener 11(1):71. https://doi.org/10.1186/s13024-016-0136-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Shah SA, Lee HY, Bressan RA, Yun DJ, Kim MO (2014) Novel osmotin attenuates glutamate-induced synaptic dysfunction and neurodegeneration via the JNK/PI3K/Akt pathway in postnatal rat brain. Cell Death Dis 5(1):e1026. https://doi.org/10.1038/cddis.2013.538

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Venkatesh K, Chivatakarn O, Sheu SS, Giger RJ (2007) Molecular dissection of the myelin-associated glycoprotein receptor complex reveals cell type-specific mechanisms for neurite outgrowth inhibition. J Cell Biol 177(3):393–399. https://doi.org/10.1083/jcb.200702102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Schwab ME (2010) Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci 11(12):799–811. https://doi.org/10.1038/nrn2936

    Article  PubMed  CAS  Google Scholar 

  27. Xu YQ, Sun ZQ, Wang YT, Xiao F, Chen MW (2015) Function of Nogo-A/Nogo-A receptor in Alzheimer’s disease. CNS neuroscience & therapeutics 21(6):479–485. https://doi.org/10.1111/cns.12387

    Article  CAS  Google Scholar 

  28. Hu F, Liu BP, Budel S, Liao J, Chin J, Fournier A, Strittmatter SM (2005) Nogo-a interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist. J Neurosci 25(22):5298–5304. https://doi.org/10.1523/JNEUROSCI.5235-04.2005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Zhu HY, Guo HF, Hou HL, Liu YJ, Sheng SL, Zhou JN (2007) Increased expression of the Nogo receptor in the hippocampus and its relation to the neuropathology in Alzheimer’s disease. Hum Pathol 38(3):426–434. https://doi.org/10.1016/j.humpath.2006.09.010

    Article  PubMed  CAS  Google Scholar 

  30. Zagrebelsky M, Korte M (2014) Maintaining stable memory engrams: new roles for Nogo-A in the CNS. Neuroscience 283:17–25. https://doi.org/10.1016/j.neuroscience.2014.08.030

    Article  PubMed  CAS  Google Scholar 

  31. Delekate A, Zagrebelsky M, Kramer S, Schwab ME, Korte M (2011) NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale. Proc Natl Acad Sci U S A 108(6):2569–2574. https://doi.org/10.1073/pnas.1013322108

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yau SY, Li A, Hoo RL, Ching YP, Christie BR, Lee TM, Xu A, So KF (2014) Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc Natl Acad Sci U S A 111(44):15810–15815. https://doi.org/10.1073/pnas.1415219111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Sakr HF (2013) Effect of sitagliptin on the working memory and reference memory in type 2 diabetic Sprague-Dawley rats: possible role of adiponectin receptors 1. J Physiol Pharmacol 64(5):613–623

    PubMed  CAS  Google Scholar 

  34. Cove J, Blinder P, Abi-Jaoude E, Lafreniere-Roula M, Devroye L, Baranes D (2006) Growth of neurites toward neurite- neurite contact sites increases synaptic clustering and secretion and is regulated by synaptic activity. Cereb Cortex 16(1):83–92. https://doi.org/10.1093/cercor/bhi086

    Article  PubMed  Google Scholar 

  35. Brenes O, Giachello CN, Corradi AM, Ghirardi M, Montarolo PG (2015) Synapsin knockdown is associated with decreased neurite outgrowth, functional synaptogenesis impairment, and fast high-frequency neurotransmitter release. J Neurosci Res 93(10):1492–1506. https://doi.org/10.1002/jnr.23624

    Article  PubMed  CAS  Google Scholar 

  36. Jahn H (2013) Memory loss in Alzheimer’s disease. Dialogues Clin Neurosci 15(4):445–454

    PubMed  PubMed Central  Google Scholar 

  37. Chen BS, Thomas EV, Sanz-Clemente A, Roche KW (2011) NMDA receptor-dependent regulation of dendritic spine morphology by SAP102 splice variants. J Neurosci 31(1):89–96. https://doi.org/10.1523/JNEUROSCI.1034-10.2011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Pak DT, Yang S, Rudolph-Correia S, Kim E, Sheng M (2001) Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron 31(2):289–303. https://doi.org/10.1016/S0896-6273(01)00355-5

    Article  PubMed  CAS  Google Scholar 

  39. Kaneko M, Xie Y, An JJ, Stryker MP, Xu B (2012) Dendritic BDNF synthesis is required for late-phase spine maturation and recovery of cortical responses following sensory deprivation. J Neurosci 32(14):4790–4802. https://doi.org/10.1523/JNEUROSCI.4462-11.2012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Takahashi H, Yamazaki H, Hanamura K, Sekino Y, Shirao T (2009) Activity of the AMPA receptor regulates drebrin stabilization in dendritic spine morphogenesis. J Cell Sci 122(Pt 8):1211–1219. https://doi.org/10.1242/jcs.043729

    Article  PubMed  CAS  Google Scholar 

  41. Kempf A, Schwab ME (2013) Nogo-A represses anatomical and synaptic plasticity in the central nervous system. Physiology 28(3):151–163. https://doi.org/10.1152/physiol.00052.2012

    Article  PubMed  CAS  Google Scholar 

  42. Karlsson TE, Karlen A, Olson L, Josephson A (2013) Neuronal overexpression of Nogo receptor 1 in APPswe/PSEN1(DeltaE9) mice impairs spatial cognition tasks without influencing plaque formation. J Alzheimers Dis 33(1):145–155. https://doi.org/10.3233/JAD-2012-120493

    Article  PubMed  CAS  Google Scholar 

  43. Teixeira AL, Diniz BS, Campos AC, Miranda AS, Rocha NP, Talib LL, Gattaz WF, Forlenza OV (2013) Decreased levels of circulating adiponectin in mild cognitive impairment and Alzheimer’s disease. NeuroMolecular Med 15(1):115–121. https://doi.org/10.1007/s12017-012-8201-2

    Article  PubMed  CAS  Google Scholar 

  44. Lin F, Lo RY, Cole D, Ducharme S, Chen DG, Mapstone M, Porsteinsson A, Alzheimer's Disease Neuroimaging I (2014) Longitudinal effects of metabolic syndrome on Alzheimer and vascular related brain pathology. Dement Geriatr Cogn Dis Extra 4(2):184–194. https://doi.org/10.1159/000363285

    Article  PubMed  PubMed Central  Google Scholar 

  45. Razay G, Vreugdenhil A, Wilcock G (2007) The metabolic syndrome and Alzheimer disease. Arch Neurol 64(1):93–96. https://doi.org/10.1001/archneur.64.1.93

    Article  PubMed  Google Scholar 

  46. Vanhanen M, Koivisto K, Moilanen L, Helkala EL, Hanninen T, Soininen H, Kervinen K, Kesaniemi YA et al (2006) Association of metabolic syndrome with Alzheimer disease: a population-based study. Neurology 67(5):843–847. https://doi.org/10.1212/01.wnl.0000234037.91185.99

    Article  PubMed  CAS  Google Scholar 

  47. Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H et al (2013) A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503(7477):493–499. https://doi.org/10.1038/nature12656

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank Jumi Park and Hyeonjeong Lee, Department of Veterinary Medicine, Gyeongsang National University, for the help using the Leica DM6000B light microscope and Qiagen Rotor Q instruments. The authors thank NIFDS for providing C57BL/6-Tg (NSE-hAPPsw) Korl mice and their information.

Funding

This research was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2016M357A1904391).

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  1. Division of Life Science and Applied Life Science (BK 21 plus), College of Natural Sciences, Gyeongsang National University, Jinju, 52828, South Korea

    Gwangho Yoon, Shahid Ali Shah, Tahir Ali & Myeong Ok Kim

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  1. Gwangho Yoon
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Contributions

G.H.Y., designed the research, performed overall experiments, and wrote manuscript, and calculation and data analysis. S.A.S. performed western blot and immunofluorescence analysis, and calculation and data analysis. T.A. revised the manuscript and performed calculation and data analysis. M.O.K. revised the manuscript and is the corresponding author and holds all the responsibilities related to this manuscript. All authors reviewed the revised manuscript.

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Correspondence to Myeong Ok Kim.

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The animal care and treatment procedures were carried out in accordance with the animal ethics committee (IACUC) guidelines issued by the Division of Applied Life Sciences at GNU, South Korea. All efforts were made to minimize the number of mice used and their suffering. The experimental approaches with mice were carried out according to the approved guidelines (Approval ID:125), and all protocols were approved by the IACUC of the Division of Applied Life Sciences, Department of Biology at GNU, South Korea.

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The authors declare that they have no conflict of interest.

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Yoon, G., Shah, S.A., Ali, T. et al. The Adiponectin Homolog Osmotin Enhances Neurite Outgrowth and Synaptic Complexity via AdipoR1/NgR1 Signaling in Alzheimer’s Disease. Mol Neurobiol 55, 6673–6686 (2018). https://doi.org/10.1007/s12035-017-0847-1

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