Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of neurons and synapses. The aim of this study was to investigate the effect of somatostatin analogue Vapreotide in an in vitro Alzheimer’s model and its effects based on the relationship between somatostatinergic transmission and neurodegenerative functions. In this study, tau transfection was performed using the MAPT gene cloned into the pcDNA3.1 vector and transfection reagent into the SH-SY5Y cell line. In viability experiments using 10 µM Memantine as a positive control, it was observed that Vapreotide at 50 µM (p < 0.0001) and 100 µM (p < 0.05) had a protective effect on cell viability, 100 µM CYN154806 was found to decrease (p < 0.05) cell viability. It was determined that Vapreotide, decreased the expression levels (50 µM-p < 0.001; 100 µM-p < 0.001; 200 µM-p < 0.0001) and phosphorylation of Tau and p-Tau proteins by western blots. With the qRT-PCR method, it was found that Vapreotide, decreased the BAX/BCL2 (50 µM-p < 0.001; 100 µM-p < 0.01; 200 µM-p < 0.001) expression level and decreased the expression level (50 µM-p < 0.01; 100 µM-p < 0.01; 200 µM-p < 0.001) of the APOE4 gene, which constitutes a genetic risk for AD. This study demonstrates a potential therapeutic role for a somatostatin analogue Vapreotide in Alzheimer’s disease.
Similar content being viewed by others
Availability of data and materials
All the data presented in the study are included in the article/Supplementary Material.
References
Ádori C, Glück L, Barde S, Yoshitake T, Kovacs GG, Mulder J, Maglóczky Z, Havas L, Bölcskei K, Mitsios N, Uhlén M, Szolcsányi J, Kehr J, Rönnbäck A, Schwartz T, Rehfeld JF, Harkany T, Palkovits M, Schulz S, Hökfelt T (2015) Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease. Acta Neuropathol 129(4):541–563. https://doi.org/10.1016/j.neuropharm.2009.06.028
Adriaensen D, Van Nassauw L, Timmermans JP (2009) The role (s) of somatostatin, structurally related peptides and somatostatin receptors in the gastrointestinal tract: a review. Regul Pept 156(1–3):1–8
Arai H, Terajima M, Miura M, Higuchi S, Muramatsu T, Machida N et al (1995) Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer’s disease. Ann Neurol: J Am Neurol Association Child Neurol Soc 38(4):649–652
Banks WA, Schally AV, Barrera CM, Fasold MB, Durham DA, Csernus VJ, Groot K, Kastin AJ (1990) Permeability of the murine blood-brain barrier to some octapeptide analogs of somatostatin. Proc Natl Acad Sci 87(17):6762–6766
Bass RT, Buckwalter BL, Patel BP, Pausch MH, Price LA, Strnad J, Hadcock JR (1996) Identification and characterization of novel somatostatin antagonists. Mol Pharmacol 50:709–715
Beltramo E, Lopatina T, Mazzeo A, Arroba AI, Valverde AM, Hernández C, Simo R, Porta M (2016) Effects of the neuroprotective drugs somatostatin and brimonidine on retinal cell models of diabetic retinopathy. Acta Diabetol 53(6):957–964
Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev 33(1):95–130. https://doi.org/10.1016/S0165-0173(00)00019-9
Burbach JPH (2010) Neuropeptides from concept to online database http://www.neuropeptides.nl. Eur J Pharmacol 626:27–48. https://doi.org/10.1016/j.ejphar.2009.10.015
Burgos-Ramos E, Hervas-Aguilar A, Aguado-Llera D, Puebla-Jiménez L, Hernández-Pinto AM, Barrios V, Arilla-Ferreiro E (2008) Somatostatin and Alzheimer’s disease. Mol Cell Endocrinol 286:104–111. https://doi.org/10.1016/j.mce.2008.01.014
Cervia D, Fiorini S, Pavan B, Biondi C, Bagnoli P (2002) Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release. Naunyn Schmiedebergs Arch Pharmacol 365(3):200–209. https://doi.org/10.1007/s00210-001-0509-7
Cheng Z, Du Z, Shang Y, Zhang Y, Zhang T (2017) A preliminary study: PS1 increases U1 snRNA expression associated with AD. J Mol Neurosci 62(3–4):269–275. https://doi.org/10.1007/s12031-017-0932-y
Chieng B, Christie MJ (2010) Somatostatin and nociceptin inhibit neurons in the central nucleus of amygdala that project to the periaqueductal grey. Neuropharmacology 59(6):425–430. https://doi.org/10.1016/j.neuropharm.2010.06.001
Craft S, Asthana S, Newcomer JW, Wilkinson CW, Matos IT, Baker LD, Cherrier M, Lofgreen, C, Latendresse S, Petrova A, Plymate S, Raskind M, Grimwood K, Veith RC (1999) Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 56(12):1135–1140. https://doi.org/10.1001/archpsyc.56.12.1135
Dehmelt L, Halpain S (2005) The MAP2/Tau family of microtubule-associated proteins. Genome Biol 6(1):1–10
Demir R, Ulvi H (2009) Alzheimer Hastalığı. Turkiye Klinikleri J Psychiatry-Special Topics 2(3):14–21
Dournaud P, Delaere P, Hauw JJ, Epelbaum J (1995) Differential correlation between neurochemical deficits, neuropathology, and cognitive status in Alzheimer’s disease. Neurobiol Aging 16:817–823. https://doi.org/10.1016/0197-4580(95)00086-T
Erdoğan MK, Sütlaş P (2004) Santral Sinir Sisteminin Dejeneratif Hastalıklarında BOS Tau Düzeylerinin Bir Belirteç Olarak Kullanımı: Bir Gözden Geçirme Yazısı. Düşünen Adam 17(2):126–130
Feniuk W, Jarvie E, Luo J, Humphrey PPA (2000) Selective somatostatin sst2 receptor blockade with the novel cyclic octapeptide, CYN-154806. Neuropharmacology 39(8):1443–1450. https://doi.org/10.1016/S0028-3908(00)00035-6
Ferjoux G, Bousquet C, Cordelier P, Benali N, Lopez F, Rochaix P et al (2000) Signal transduction of somatostatin receptors negatively controlling cell proliferation. J Physiol Paris 94(3):205–210. https://doi.org/10.1016/S0928-4257(00)00206-0
Goedert M, Jakes R, Crowther RA, Six J, Lübke U, Vandermeeren M et al (1993) The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci 190(11):5066–5070. https://doi.org/10.1073/pnas.90.11.5066
Hanger DP, Anderton BH, Noble W (2009) Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med 15:112–119. https://doi.org/10.1016/j.molmed.2009.01.003
Hannon JP, Nunn C, Stolz B, Bruns C, Weckbecker G, Lewis I et al (2002) Drug design at peptide receptors. J Mol Neurosci 18(1–2):15–27
Holliday ND, Tough IR, Cox HM (2007) A functional comparison of recombinant and native somatostatin sst2 receptor variants in epithelia. Br J Pharmacol 152(1):132–140. https://doi.org/10.1038/sj.bjp.0707365
Hoyer D, Lübbert H, Bruns C (1994) Molecular pharmacology of somatostatin receptors. Naunyn Schmiedebergs Arch Pharmacol 350(5):441–453
Kayaalp O (2009) Rasyonel Tedavi Yönünden Tıbbi Farmakoloji. 12. baskı, 1. cilt. Pelikan Yayıncılık, Ankara, pp 85–87
Kiagiadaki F, Savvaki M, Thermos K (2010) Activation of somatostatin receptor (sst5) protects the rat retina from AMPA-induced neurotoxicity. Neuropharmacology 58(1):297–303. https://doi.org/10.1016/j.neuropharm.2009.06.028
Koca D, Hastar N, Engür S, Kiraz Y, Ulu GT, Çekdemir D, Baran Y (2020) Therapeutic potentials of inhibition of Jumonji C domain-containing demethylases in acute myeloid leukemia. Turkish Journal of Hematology 37(1):5
Kowall NW, Beal MF (1988) Cortical somatostatin, neuropeptide Y, and NADPH diaphorase neurons: normal anatomy and alterations in Alzheimer’s disease. Ann Neurol 23:105–114. https://doi.org/10.1002/ana.410230202
Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, Belle G, Jolley L, Larson EB (2002) Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 59(11):1737–1746. https://doi.org/10.1001/archneur.59.11.1737
Kumar R, Verma V, Jain A, Jain RK, Maikhuri JP, Gupta G (2011) Synergistic chemoprotective mechanisms of dietary phytoestrogens in a select combination against prostate cancer. J Nutr Biochem 22(8):723–731
Liu X, Ou S, Yin M, Xu T, Wang T, Liu Y et al (2017) N-methyl-D-aspartate receptors mediate epilepsy-induced axonal impairment and tau phosphorylation via activating glycogen synthase kinase-3b and cyclindependent kinase 5. Discov Med 23:221–234
Lu XT, Wang H, Jia ZJ, Li QY, Niu Q (2017) The effect of aluminum trichloride on expression of phosphorylated tau and Aβ in SH-SY5Y cells. Chin J Ind Hyg Occup Dis 35(5):359–361. https://doi.org/10.3760/cma.j.issn.1001-9391.2017.05.011
Mackay EA, Ehrhard A, Moniatte M, Guenet C, Tardif C, Tarnus C et al (1997) A possible role for cathepsins D, E, and B in the processing of beta-amyloid precursor protein in Alzheimer’s disease. Eur J Biochem 244:414–425
Mancillas JR, Siggins GR, Bloom FE (1986) Somatostatin selectively enhances acetylcholine-induced excitations in rat hippocampus and cortex. Proc Natl Acad Sci 83(19):7518–7521. https://doi.org/10.1073/pnas.83.19.7518
Martel G, Dutar P, Epelbaum J, Viollet C (2012) Somatostatinergic systems: an update on brain functions in normal and pathological aging. Front Endocrinol 3:154
Matsuoka N, Kaneko S, Satoh M (1991) Somatostatin augments long-term potentiation of the mossy fiber-CA3 system in guinea-pig hippocampal slices. Brain Res 553(2):188–194. https://doi.org/10.1016/0006-8993(91)90823-E
Matsuoka N, Maeda N, Yamaguchi I, Satoh M (1994) Possible involvement of brain somatostatin in the memory formation of rats and the cognitive enhancing action of FR121196 in passive avoidance task. Brain Res 642(1):11–19. https://doi.org/10.1016/0006-8993(94)90900-8
Mookherjee P, Quintanilla R, Roh MS, Zmijewska AA, Jope RS, Johnson GV (2007) Mitochondrial-targeted active Akt protects SH-SY5Y neuroblastoma cells from staurosporine-induced apoptotic cell death. J Cell Biochem 102(1):196–210. https://doi.org/10.1002/jcb.21287
Mullane K, Williams M (2018) Alzheimer’s disease (AD) therapeutics–2: beyond amyloid–re-defining AD and its causality to discover effective therapeutics. Biochem Pharmacol 158:376–401. https://doi.org/10.1016/j.bcp.2018.09.027
Nilsson CL, Brinkmalm A, Minthon L, Blennow K, Ekman R (2001) Processing of neuropeptide Y, galanin, and somatostatin in the cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia. Peptides 22(12):2105–2112. https://doi.org/10.1016/S0196-9781(01)00571-X
Nunn C, Cervia D, Bouhelal R, Hoyer D (2003a) Differential modulation of intracellular Ca2+ and luciferase expression via the human somatostatin sst2 receptor. Neuropeptides 37:159–199
Nunn C, Schoeffter P, Langenegger D, Hoyer D (2003b) Functional characterisation of the putative somatostatin sst 2 receptor antagonist CYN154806. Naunyn Schmiedebergs Arch Pharmacol 367(1):1–9. https://doi.org/10.1007/s00210-002-0656-5
Ostasiewicz B, Ostasiewicz P, Duś-Szachniewicz K, Ostasiewicz K, Ziółkowski P (2016) Quantitative analysis of gene expression in fixed colorectal carcinoma samples as a method for biomarker validation. Mol Med Rep 13(6):5084–5092. https://doi.org/10.3892/mmr.2016.5200
Ozansoy M, Başak AN (2007) Taupatiler: Nörodejeneratif Hastalıkların Özgün bir Türü. Türk Nöroloji Dergisi 13(1):1–29
Perez J, Hoyer D (1995) Co-expression of somatostatin SSTR-3 and SSTR-4 receptor messenger RNAs in the rat brain. Neuroscience 64(1):241–253. https://doi.org/10.1016/0306-4522(94)00364-B
Rai U, Thrimawithana TR, Valery C, Young SA (2015) Therapeutic uses of somatostatin and its analogues: current view and potential applications. Pharmacol Ther 152:98–110. https://doi.org/10.1016/j.pharmthera.2015.05.007
Schettini G, Florio T, Magri G, Grimaldi M, Meucci O, Landolfi E, Marino A (1988) Somatostatin and SMS 201–995 reverse the impairment of cognitive functions induced by cysteamine depletion of brain somatostatin. Eur J Pharmacol 151(3):399–407. https://doi.org/10.1016/0014-2999(88)90536-5
Song MS, Rauw G, Baker GB, Kar S (2008) Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation. Eur J Neurosci 28(10):1989–2002. https://doi.org/10.1111/j.1460-9568.2008.06498.x
Song YH, Yoon J, Lee SH (2021) The role of neuropeptide somatostatin in the brain and its application in treating neurological disorders. Exp Mol Med 53(3):328–338
Spitsin S, Tuluc F, Meshki J, Lai JP, Tustin Iii R, Douglas SD (2013) Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor. NeuroImmunoModulation 20(5):247–255. https://doi.org/10.1159/000350468
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci 90(5):1977–1981. https://doi.org/10.1073/pnas.90.5.1977
Urcan E, Haertel U, Styllou M, Hickel R, Scherthan H, Reichl FX (2010) Real-time xCELLigence impedance analysis of the cytotoxicity of dental composite components on human gingival fibroblasts. Dent Mater 26(1):51–58. https://doi.org/10.1016/j.dental.2009.08.007
Viollet C, Lepousez G, Loudes C, Videau C, Simon A, Epelbaum J (2008) Somatostatinergic systems in brain: networks and functions. Mol Cell Endocrinol 286:75–87. https://doi.org/10.1016/j.mce.2007.09.007
Wang JZ, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25:59–68. https://doi.org/10.1111/j.1460-9568.2006.05226.x
Wilson RS, Martin EM (1988) New intrathecal drugs in Alzheimer’s disease and psychometric testing. Ann N Y Acad Sci 531(1):180–186
Wittenauer R, Smith L, Aden K Update on 2004 background paper written by Saloni Tanna, Pharm. D. MPH Background Paper, 6.
Yoon SY, Park JS, Choi JE, Choi JM, Lee WJ, Kim SW, Kim DH (2010) Rosiglitazone reduces tau phosphorylation via JNK inhibition in the hippocampus of rats with type 2 diabetes and tau transfected SH-SY5Y cells. Neurobiol Dis 40(2):449–455. https://doi.org/10.1016/j.nbd.2010.07.005
Zhao X, Jones A, Olson KR, Peng K, Wehrman T, Park A, Mallari R, Nebalasca D, Young SW, Xiao SH (2008) A homogeneous enzyme fragment complementation-based β-arrestin translocation assay for high-throughput screening of G-protein-coupled receptors. J Biomol Screen 13(8):737–747. https://doi.org/10.1177/1087057108321531
Funding
This work was supported by the Erciyes University Scientific Research Projects Coordination Unit under Grant number TDK-2017–7674.
Author information
Authors and Affiliations
Contributions
EU and MBY conceived and designed research. EU conducted experiments. EU and MBY analyzed data. EU wrote the manuscript. All authors read and approved the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
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.
About this article
Cite this article
Uzunhisarcıklı, E., Yerer, M.B. Neuroprotective Effects of Vapreotide on Tau Transfection–Induced Neurodegeneration. Neurotox Res 40, 1824–1837 (2022). https://doi.org/10.1007/s12640-022-00588-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-022-00588-2