Skip to main content

Advertisement

SpringerLink
Log in

Investigation of Cyclo-Z Therapeutic Effect on Insulin Pathway in Alzheimer's Rat Model: Biochemical and Electrophysiological Parameters

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Cyclo (his-pro-CHP) plus zinc (Zn+2) (Cyclo-Z) is the only known chemical that increases the production of insulin-degrading enzyme (IDE) and decreases the number of inactive insulin fragments in cells. The aim of the present study was to systematically characterize the effects of Cyclo-Z on the insulin pathway, memory functions, and brain oscillations in the Alzheimer's disease (AD) rat model. The rat model of AD was established by bilateral injection of Aβ42 oligomer (2,5nmol/10μl) into the lateral ventricles. Cyclo-Z (10mg Zn+2/kg and 0.2mg CHP/kg) gavage treatment started seven days after Aβ injection and lasted for 21 days. At the end of the experimental period, memory tests and electrophysiological recordings were performed, which were followed by the biochemical analysis. Aβ42 oligomers led to a significant increase in fasting blood glucose, serum insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and phospho-tau-Ser356 levels. Moreover, Aβ42 oligomers caused a significant decrement in body weight, hippocampal insulin, brain insulin receptor substrate (IRS-Ser612), and glycogen synthase kinase-3 beta (GSK-3β) levels. Also, Aβ42 oligomers resulted in a significant reduction in memory. The Cyclo-Z treatment prevented the observed alterations in the ADZ group except for phospho-tau levels and attenuated the increased Aβ42 oligomer levels in the ADZ group. We also found that the Aβ42 oligomer decreased the left temporal spindle and delta power during ketamine anesthesia. Cyclo-Z treatment reversed the Aβ42 oligomer-related alterations in the left temporal spindle power. Cyclo-Z prevents Aβ oligomer-induced changes in the insulin pathway and amyloid toxicity, and may contribute to the improvement of memory deficits and neural network dynamics in this rat model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

References

  1. Song MK, Bischoff DS, Song AM, Uyemura K, Yamaguchi DT (2017) Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment. BBA Clin 7:41–54. https://doi.org/10.1016/j.bbacli.2016.09.003S2214-6474(16)30039-3

    Article  PubMed  Google Scholar 

  2. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I et al (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95(11):6448–6453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880):535–539. https://doi.org/10.1038/416535a416535a]

    Article  CAS  PubMed  Google Scholar 

  4. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14(8):837–842. https://doi.org/10.1038/nm1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440(7082):352–357. https://doi.org/10.1038/nature04533

    Article  CAS  PubMed  Google Scholar 

  6. Miyauchi T, Hagimoto H, Ishii M, Endo S, Tanaka K, Kajiwara S, Endo K, Kajiwara A et al (1994) Quantitative EEG in patients with presenile and senile dementia of the Alzheimer type. Acta Neurol Scand 89(1):56–64

    Article  CAS  PubMed  Google Scholar 

  7. Brunovsky M, Matousek M, Edman A, Cervena K, Krajca V (2003) Objective assessment of the degree of dementia by means of EEG. Neuropsychobiology 48(1):19–26. https://doi.org/10.1159/000071824

    Article  PubMed  Google Scholar 

  8. de la Monte SM, Wands JR (2005) Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J Alzheimers Dis 7(1):45–61. https://doi.org/10.3233/jad-2005-7106

    Article  PubMed  Google Scholar 

  9. Schuh AF, Rieder CM, Rizzi L, Chaves M, Roriz-Cruz M (2011) Mechanisms of brain aging regulation by insulin: implications for neurodegeneration in late-onset Alzheimer's disease. ISRN Neurol 2011:306905. https://doi.org/10.5402/2011/306905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112. https://doi.org/10.1038/nrm2101

    Article  CAS  PubMed  Google Scholar 

  11. Ferreira ST, Vieira MN, De Felice FG (2007) Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases. IUBMB Life 59(4-5):332–345. https://doi.org/10.1080/15216540701283882

    Article  CAS  PubMed  Google Scholar 

  12. Ferreira ST, Klein WL (2011) The Abeta oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease. Neurobiol Learn Mem 96(4):529–543. https://doi.org/10.1016/j.nlm.2011.08.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R (2002) Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 22(10):RC221

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J 22(1):246–260. https://doi.org/10.1096/fj.06-7703com

    Article  CAS  PubMed  Google Scholar 

  15. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ et al (2009) Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A 106(6):1971–1976. https://doi.org/10.1073/pnas.0809158106

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lane RF, Shineman DW, Steele JW, Lee LB, Fillit HM (2012) Beyond amyloid: the future of therapeutics for Alzheimer's disease. Adv Pharmacol 64:213–271. https://doi.org/10.1016/B978-0-12-394816-8.00007-6

    Article  CAS  PubMed  Google Scholar 

  17. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci 27(4):796–807. https://doi.org/10.1523/JNEUROSCI.3501-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Escribano L, Simon AM, Gimeno E, Cuadrado-Tejedor M, Lopez de Maturana R, Garcia-Osta A, Ricobaraza A, Perez-Mediavilla A et al (2010) Rosiglitazone rescues memory impairment in Alzheimer's transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology 35(7):1593–1604. https://doi.org/10.1038/npp.2010.32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jha NK, Jha SK, Kumar D, Kejriwal N, Sharma R, Ambasta RK, Kumar P (2015) Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer's Disease Biology: Characterization of Putative Cognates for Therapeutic Applications. J Alzheimers Dis 48(4):891–917. https://doi.org/10.3233/JAD-150379

    Article  CAS  PubMed  Google Scholar 

  20. Pivovarova O, Hohn A, Grune T, Pfeiffer AF, Rudovich N (2016) Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer's disease? Ann Med 48(8):614–624. https://doi.org/10.1080/07853890.2016.1197416

    Article  CAS  PubMed  Google Scholar 

  21. Morales-Corraliza J, Wong H, Mazzella MJ, Che S, Lee SH, Petkova E, Wagner JD, Hemby SE et al (2016) Brain-Wide Insulin Resistance, Tau Phosphorylation Changes, and Hippocampal Neprilysin and Amyloid-beta Alterations in a Monkey Model of Type 1 Diabetes. J Neurosci 36(15):4248–4258. https://doi.org/10.1523/JNEUROSCI.4640-14.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Miao X, Sun W, Fu Y, Miao L, Cai L (2013) Zinc homeostasis in the metabolic syndrome and diabetes. Front Med 7(1):31–52. https://doi.org/10.1007/s11684-013-0251-9

    Article  PubMed  Google Scholar 

  23. Lifshitz V, Benromano T, Weiss R, Blanga-Kanfi S, Frenkel D (2013) Insulin-degrading enzyme deficiency accelerates cerebrovascular amyloidosis in an animal model. Brain Behav Immun 30:143–149. https://doi.org/10.1016/j.bbi.2012.12.003

    Article  CAS  PubMed  Google Scholar 

  24. Roberts RO, Knopman DS, Geda YE, Cha RH, Pankratz VS, Baertlein L, Boeve BF, Tangalos EG et al (2014) Association of diabetes with amnestic and nonamnestic mild cognitive impairment. Alzheimers Dement 10(1):18–26. https://doi.org/10.1016/j.jalz.2013.01.001

    Article  PubMed  Google Scholar 

  25. Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, de Boer IH (2016) Clinical Manifestations of Kidney Disease Among US Adults With Diabetes, 1988-2014. JAMA 316(6):602–610. https://doi.org/10.1001/jama.2016.10924

    Article  PubMed  PubMed Central  Google Scholar 

  26. Watt NT, Whitehouse IJ, Hooper NM (2010) The role of zinc in Alzheimer's disease. Int J Alzheimers Dis 2011:971021. https://doi.org/10.4061/2011/971021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Borza DB, Morgan WT (1998) Histidine-proline-rich glycoprotein as a plasma pH sensor. Modulation of its interaction with glycosaminoglycans by ph and metals. J Biol Chem 273(10):5493–5499. https://doi.org/10.1074/jbc.273.10.5493

    Article  CAS  PubMed  Google Scholar 

  28. Rosenthal MJ, Hwang IK, Song MK (2001) Effects of arachidonic acid and cyclo (his-pro) on zinc transport across small intestine and muscle tissues. Life Sci 70(3):337–348. https://doi.org/10.1016/s0024-3205(01)01395-9

    Article  CAS  PubMed  Google Scholar 

  29. Maher PA, Schubert DR (2009) Metabolic links between diabetes and Alzheimer's disease. Expert Rev Neurother 9(5):617–630. https://doi.org/10.1586/ern.09.18

    Article  CAS  PubMed  Google Scholar 

  30. Banks WA, Kastin AJ, Jaspan JB (1992) Orally administered cyclo(His-Pro) reduces ethanol-induced narcosis in mice. Pharmacol Biochem Behav 43(3):939–941. https://doi.org/10.1016/0091-3057(92)90428-i

    Article  CAS  PubMed  Google Scholar 

  31. Banks WA, Kastin AJ, Akerstrom V, Jaspan JB (1993) Radioactively iodinated cyclo(His-Pro) crosses the blood-brain barrier and reverses ethanol-induced narcosis. Am J Physiol 264(5 Pt 1):E723–E729. https://doi.org/10.1152/ajpendo.1993.264.5.E723

    Article  CAS  PubMed  Google Scholar 

  32. Jaspan JB, Banks WA, Kastin AJ (1994) Study of passage of peptides across the blood-brain barrier: biological effects of cyclo(His-Pro) after intravenous and oral administration. Ann N Y Acad Sci 739:101–107. https://doi.org/10.1111/j.1749-6632.1994.tb19811.x

    Article  CAS  PubMed  Google Scholar 

  33. Song MK, Rosenthal MJ, Song AM, Uyemura K, Yang H, Ament ME, Yamaguchi DT, Cornford EM (2009) Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro). Br J Pharmacol 158(2):442–450. https://doi.org/10.1111/j.1476-5381.2009.00201.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang X, Hu X, Yang Y, Takata T, Sakurai T (2015) Systemic pyruvate administration markedly reduces neuronal death and cognitive impairment in a rat model of Alzheimer's disease. Exp Neurol 271:145–154. https://doi.org/10.1016/j.expneurol.2015.06.008

    Article  CAS  PubMed  Google Scholar 

  35. Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, Tweedie D, Perry T et al (2010) GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. J Alzheimers Dis 19(4):1205–1219. https://doi.org/10.3233/JAD-2010-1314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gong L, Li SL, Li H, Zhang L (2011) Ginsenoside Rg1 protects primary cultured rat hippocampal neurons from cell apoptosis induced by beta-amyloid protein. Pharm Biol 49(5):501–507. https://doi.org/10.3109/13880209.2010.521514

    Article  CAS  PubMed  Google Scholar 

  37. Yang S, Chen Z, Cao M, Li R, Wang Z, Zhang M (2017) Pioglitazone ameliorates Abeta42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3beta activation. Mol Med Rep 15(5):2588–2594. https://doi.org/10.3892/mmr.2017.6342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Roozendaal B, Hernandez A, Cabrera SM, Hagewoud R, Malvaez M, Stefanko DP, Haettig J, Wood MA (2010) Membrane-associated glucocorticoid activity is necessary for modulation of long-term memory via chromatin modification. J Neurosci 30(14):5037–5046. https://doi.org/10.1523/JNEUROSCI.5717-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kshirsagar V, Thingore C, Juvekar A (2021) Insulin resistance: a connecting link between Alzheimer's disease and metabolic disorder. Metab Brain Dis 36(1):67–83. https://doi.org/10.1007/s11011-020-00622-2

    Article  PubMed  Google Scholar 

  40. James D, Kang S, Park S (2014) Injection of beta-amyloid into the hippocampus induces metabolic disturbances and involuntary weight loss which may be early indicators of Alzheimer's disease. Aging Clin Exp Res 26(1):93–98. https://doi.org/10.1007/s40520-013-0181-z

    Article  PubMed  Google Scholar 

  41. Craft S, Newcomer J, Kanne S, Dagogo-Jack S, Cryer P, Sheline Y, Luby J, Dagogo-Jack A et al (1996) Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiol Aging 17(1):123–130. https://doi.org/10.1016/0197-4580(95)02002-0

    Article  CAS  PubMed  Google Scholar 

  42. Zhao H, Wu C, Zhang X, Wang L, Sun J, Zhuge F (2019) Insulin Resistance Is a Risk Factor for Mild Cognitive Impairment in Elderly Adults with T2DM. Open Life Sci 14:255–261. https://doi.org/10.1515/biol-2019-0029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sano H, Eguez L, Teruel MN, Fukuda M, Chuang TD, Chavez JA, Lienhard GE, McGraw TE (2007) Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell Metab 5(4):293–303. https://doi.org/10.1016/j.cmet.2007.03.001

    Article  CAS  PubMed  Google Scholar 

  44. Rui L (2014) Energy metabolism in the liver. Compr Physiol 4(1):177–197. https://doi.org/10.1002/cphy.c130024

    Article  PubMed  PubMed Central  Google Scholar 

  45. Velazquez R, Tran A, Ishimwe E, Denner L, Dave N, Oddo S, Dineley KT (2017) Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease. Neurobiol Aging 58:1–13. https://doi.org/10.1016/j.neurobiolaging.2017.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang Y, Yang R, Gu J, Yin X, Jin N, Xie S, Wang Y, Chang H et al (2015) Cross talk between PI3K-AKT-GSK-3beta and PP2A pathways determines tau hyperphosphorylation. Neurobiol Aging 36(1):188–200. https://doi.org/10.1016/j.neurobiolaging.2014.07.035

    Article  CAS  PubMed  Google Scholar 

  47. Lauretti E, Dincer O (2020) Glycogen synthase kinase-3 signaling in Alzheimer’s disease. Biochim Biophys Acta Mol Cell Res 1867(5):118664. https://doi.org/10.1016/j.bbamcr.2020.118664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li X, Song D, Leng SX (2015) Link between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment. Clin Interv Aging 10:549–560. https://doi.org/10.2147/CIA.S74042

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ahmad W (2013) Overlapped metabolic and therapeutic links between Alzheimer and diabetes. Mol Neurobiol 47(1):399–424. https://doi.org/10.1007/s12035-012-8352-z

    Article  CAS  PubMed  Google Scholar 

  50. Ando K, Maruko-Otake A, Ohtake Y, Hayashishita M, Sekiya M, Iijima KM (2016) Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Abeta42-Induced Tau Toxicity. PLoS Genet 12(3):e1005917. https://doi.org/10.1371/journal.pgen.1005917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H (2002) Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem 9(2):49–57. https://doi.org/10.1101/lm.41302

    Article  PubMed  PubMed Central  Google Scholar 

  52. Haettig J, Stefanko DP, Multani ML, Figueroa DX, McQuown SC, Wood MA (2011) HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner. Learn Mem 18(2):71–79. https://doi.org/10.1101/lm.1986911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rozema NB, Procissi D, Bertolino N, Viola KL, Nandwana V, Abdul N, Pribus S, Dravid V et al (2020) Abeta oligomer induced cognitive impairment and evaluation of ACU193-MNS-based MRI in rabbit. Alzheimers Dement 6(1):e12087. https://doi.org/10.1002/trc2.12087

    Article  Google Scholar 

  54. Kim DH, Choi SM, Jho J, Park MS, Kang J, Park SJ, Ryu JH, Jo J et al (2016) Infliximab ameliorates AD-associated object recognition memory impairment. Behav Brain Res 311:384–391. https://doi.org/10.1016/j.bbr.2016.06.001

    Article  CAS  PubMed  Google Scholar 

  55. Bermudez-Rattoni F, Okuda S, Roozendaal B, McGaugh JL (2005) Insular cortex is involved in consolidation of object recognition memory. Learn Mem 12(5):447–449. https://doi.org/10.1101/lm.97605

    Article  PubMed  Google Scholar 

  56. Balderas I, Rodriguez-Ortiz CJ, Salgado-Tonda P, Chavez-Hurtado J, McGaugh JL, Bermudez-Rattoni F (2008) The consolidation of object and context recognition memory involve different regions of the temporal lobe. Learn Mem 15(9):618–624. https://doi.org/10.1101/lm.1028008

    Article  PubMed  PubMed Central  Google Scholar 

  57. Winters BD, Forwood SE, Cowell RA, Saksida LM, Bussey TJ (2004) Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe. J Neurosci 24(26):5901–5908. https://doi.org/10.1523/JNEUROSCI.1346-04.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Winters BD, Bussey TJ (2005) Transient inactivation of perirhinal cortex disrupts encoding, retrieval, and consolidation of object recognition memory. J Neurosci 25(1):52–61. https://doi.org/10.1523/JNEUROSCI.3827-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Akirav I, Maroun M (2006) Ventromedial prefrontal cortex is obligatory for consolidation and reconsolidation of object recognition memory. Cereb Cortex 16(12):1759–1765. https://doi.org/10.1093/cercor/bhj114

    Article  PubMed  Google Scholar 

  60. Yamamoto N, Ishikuro R, Tanida M, Suzuki K, Ikeda-Matsuo Y, Sobue K (2018) Insulin-signaling Pathway Regulates the Degradation of Amyloid beta-protein via Astrocytes. Neuroscience 385:227–236. https://doi.org/10.1016/j.neuroscience.2018.06.018

    Article  CAS  PubMed  Google Scholar 

  61. Zhao Z, Xiang Z, Haroutunian V, Buxbaum JD, Stetka B, Pasinetti GM (2007) Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging 28(6):824–830. https://doi.org/10.1016/j.neurobiolaging.2006.05.001

    Article  CAS  PubMed  Google Scholar 

  62. Stargardt A, Gillis J, Kamphuis W, Wiemhoefer A, Kooijman L, Raspe M, Benckhuijsen W, Drijfhout JW et al (2013) Reduced amyloid-beta degradation in early Alzheimer's disease but not in the APPswePS1dE9 and 3xTg-AD mouse models. Aging Cell 12(3):499–507. https://doi.org/10.1111/acel.12074

    Article  CAS  PubMed  Google Scholar 

  63. Sikanyika NL, Parkington HC, Smith AI, Kuruppu S (2019) Powering Amyloid Beta Degrading Enzymes: A Possible Therapy for Alzheimer's Disease. Neurochem Res 44(6):1289–1296. https://doi.org/10.1007/s11064-019-02756-x

    Article  CAS  PubMed  Google Scholar 

  64. Song MK, Rosenthal MJ, Naliboff BD, Phanumas L, Kang KW (1998) Effects of bovine prostate powder on zinc, glucose, and insulin metabolism in old patients with non-insulin-dependent diabetes mellitus. Metabolism 47(1):39–43. https://doi.org/10.1016/s0026-0495(98)90190-1

    Article  CAS  PubMed  Google Scholar 

  65. Song MK, Rosenthal MJ, Hong S, Harris DM, Hwang I, Yip I, Golub MS, Ament ME et al (2001) Synergistic antidiabetic activities of zinc, cyclo (his-pro), and arachidonic acid. Metabolism 50(1):53–59. https://doi.org/10.1053/meta.2001.19427

    Article  CAS  PubMed  Google Scholar 

  66. Hwang IK, Go VL, Harris DM, Yip I, Kang KW, Song MK (2003) Effects of cyclo (his-pro) plus zinc on glucose metabolism in genetically diabetic obese mice. Diabetes Obes Metab 5(5):317–324. https://doi.org/10.1046/j.1463-1326.2003.00281.x

    Article  CAS  PubMed  Google Scholar 

  67. Song MK, Hwang IK, Rosenthal MJ, Harris DM, Yamaguchi DT, Yip I, Go VL (2003) Anti-hyperglycemic activity of zinc plus cyclo (his-pro) in genetically diabetic Goto-Kakizaki and aged rats. Exp Biol Med (Maywood) 228(11):1338–1345. https://doi.org/10.1177/153537020322801112

    Article  CAS  PubMed  Google Scholar 

  68. Song MK, Rosenthal MJ, Song AM, Yang H, Ao Y, Yamaguchi DT (2005) Raw vegetable food containing high cyclo (his-pro) improved insulin sensitivity and body weight control. Metabolism 54(11):1480–1489. https://doi.org/10.1016/j.metabol.2005.05.014

    Article  CAS  PubMed  Google Scholar 

  69. Paz K, Liu YF, Shorer H, Hemi R, LeRoith D, Quan M, Kanety H, Seger R et al (1999) Phosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function. J Biol Chem 274(40):28816–28822. https://doi.org/10.1074/jbc.274.40.28816

    Article  CAS  PubMed  Google Scholar 

  70. Sun W, Yang J, Wang W, Hou J, Cheng Y, Fu Y, Xu Z, Cai L (2018) The beneficial effects of Zn on Akt-mediated insulin and cell survival signaling pathways in diabetes. J Trace Elem Med Biol 46:117–127. https://doi.org/10.1016/j.jtemb.2017.12.005

    Article  CAS  PubMed  Google Scholar 

  71. Shirotani K, Tsubuki S, Iwata N, Takaki Y, Harigaya W, Maruyama K, Kiryu-Seo S, Kiyama H et al (2001) Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem 276(24):21895–21901. https://doi.org/10.1074/jbc.M008511200

    Article  CAS  PubMed  Google Scholar 

  72. Lazarewicz MT, Ehrlichman RS, Maxwell CR, Gandal MJ, Finkel LH, Siegel SJ (2010) Ketamine modulates theta and gamma oscillations. J Cogn Neurosci 22(7):1452–1464. https://doi.org/10.1162/jocn.2009.21305

    Article  PubMed  Google Scholar 

  73. Ladenbauer J, Ladenbauer J, Kulzow N, de Boor R, Avramova E, Grittner U, Floel A (2017) Promoting Sleep Oscillations and Their Functional Coupling by Transcranial Stimulation Enhances Memory Consolidation in Mild Cognitive Impairment. J Neurosci 37(30):7111–7124. https://doi.org/10.1523/JNEUROSCI.0260-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mander BA (2020) Local Sleep and Alzheimer's Disease Pathophysiology. Front Neurosci 14:525970. https://doi.org/10.3389/fnins.2020.525970

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zhurakovskaya E, Ishchenko I, Gureviciene I, Aliev R, Grohn O, Tanila H (2019) Impaired hippocampal-cortical coupling but preserved local synchrony during sleep in APP/PS1 mice modeling Alzheimer's disease. Sci Rep 9(1):5380. https://doi.org/10.1038/s41598-019-41851-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ji X, Liu J (2015) Associations between Blood Zinc Concentrations and Sleep Quality in Childhood: A Cohort Study. Nutrients 7(7):5684–5696. https://doi.org/10.3390/nu7075247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee YF, Gerashchenko D, Timofeev I, Bacskai BJ, Kastanenka KV (2020) Slow Wave Sleep Is a Promising Intervention Target for Alzheimer's Disease. Front Neurosci 14:705. https://doi.org/10.3389/fnins.2020.00705

    Article  PubMed  PubMed Central  Google Scholar 

  78. Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, Fagan AM, McCue L et al (2019) Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease. Sci Transl Med 11(474). https://doi.org/10.1126/scitranslmed.aau6550

Download references

Acknowledgements

Not applicaple.

Funding

This study was supported by a grant from Akdeniz University Research Foundation, Turkey (Grant No: TDK-2018-3272).

Author information

Authors and Affiliations

  1. Department of Biophysics, Faculty of Medicine, Akdeniz University, Arapsuyu, 07070, Antalya, Turkey

    Alev Duygu Acun, Deniz Kantar, Orhan Erkan, Narin Derin & Piraye Yargıcoglu

  2. Department of Medical Imaging Techniques, Vocational School of Health Services, Akdeniz University, Arapsuyu, 07070, Antalya, Turkey

    Hakan Er

Authors
  1. Alev Duygu Acun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deniz Kantar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hakan Er
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Orhan Erkan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Narin Derin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Piraye Yargıcoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ADA, DK and HE generated the rat models, recorded and analyzed EEG, and were involved in the study design. ADA and OE analyzed the western blot data. All the authors previously mentioned, as well as ND and PY, were involved in data interpretation, critically reviewed and provided their final approval of the manuscript, and agreed to be accountable for the work.

Corresponding author

Correspondence to Alev Duygu Acun.

Ethics declarations

Conflict of Interest

The authors report no conflicts of interest in this work.

Ethics Approval

Ethical approval for this work was obtained from Akdeniz University Local Committee on Animal Research Ethics (ethics approval date and number: 26.01.2018/2018.01.014-17).

Consent to Participate

Not applicaple.

Consent for Publication

Not applicaple.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Acun, A.D., Kantar, D., Er, H. et al. Investigation of Cyclo-Z Therapeutic Effect on Insulin Pathway in Alzheimer's Rat Model: Biochemical and Electrophysiological Parameters. Mol Neurobiol 60, 4030–4048 (2023). https://doi.org/10.1007/s12035-023-03334-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03334-7

Keywords

Search

Navigation