Combined vildagliptin and memantine treatment downregulates expression of amyloid precursor protein, and total and phosphorylated tau in a rat model of combined Alzheimer’s disease and type 2 diabetes

  • Samar S. KhalafEmail author
  • Mohamed M. Hafez
  • Eman T. Mehanna
  • Noha M. Mesbah
  • Dina M. Abo-Elmatty
Original Article


There is increasing evidence of a link between type 2 diabetes mellitus (T2DM) and cognitive decline. T2DM has been recognized as a risk factor for Alzheimer’s disease (AD). The aim of this research was to investigate the biochemical and physiological effects of vildagliptin treatment alone, and in combination with memantine, in a rat model of combined T2DM and AD. The experimental study was carried out on 75 male Wistar rats weighing 180–200 g. The rats were divided into five groups (n = 15): normal group, Alzheimer diabetic control, treated with vildagliptin (10 mg/kg/day), treated with memantine (30 mg/kg/day), and treated with combination of drugs. Serum glucose, lipid profile, acetylcholinesterase (AChE), homocysteine (Hcy), and amyloid beta peptide (Aβ) were determined. Lipid peroxidation was measured in brain tissue. Expression of amyloid precursor protein (APP) in the brain was assessed by q-PCR, and expression of total and phosphorylated tau was determined by Western Blotting. Vildagliptin alone and in combination with memantine caused a decrease in blood glucose, HOMA-IR, lipid profile, Hcy, malanodialdhyde, and acetylcholinesterase, and an increase in apolipoprotein E. Expression of APP and phosphorylated tau protein was decreased with combined vildagliptin and memantine treatment. In conclusion, vildagliptin treatment, either alone or in combination with memantine, modulates AD-associated biochemical changes and downregulates amyloid precursor protein and phosphorylated tau expression in diabetic rats.


Alzheimer’s disease Diabetes mellitus Vildagliptin Memantine Amyloid beta peptide Tau protein 





Alzheimer disease


Advanced glycation end products


Apolipopreotein E


Amyloid precursor protein

Amyloid beta peptide


β-site Aβ precursorprotein-cleaving enzyme 1


Blood glucose


Central nervous system


Dipeptidyl peptidase-4


Glucose-dependent insolinotropic polypeptide


Glucagon-like peptide-1


Glucose transport protein 3


Glycogen synthase kinase-3 beta




High-density lipoprotein


Low-density lipoprotein cholesterol


Lipid peroxidation




Nuclear factor kappa-light-chain-enhancer of activated β cells




Phosphate-buffered saline


Phospho tau antibody


Phosphoseryl/phosphothreonyl protein phosphatase-2A


Reactive oxygen species




Type 2diabetes mellitus




Total cholesterol


Transforming growth factor beta-1


Authors’ contributions

Dina M. Abo-Elmatty and Noha M. Mesbah designed the study. Samar S. Khalaf and Mohamed M. Hafez were responsible for the laboratory work. Samar S. Khalaf, Mohamed M. Hafez, and Eman T. Mehanna interpreted the results and carried out statistical analysis. All authors contributed to the manuscript writing.

Compliance with ethical standards

The study protocol was approved by the Ethics Committee of the Faculty of Pharmacy, Suez Canal University (code # 201703RA2).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abdelsalam RM, Safar MM (2015) Neuroprotective effects of vildagliptin in rat rotenone Parkinson’s disease model: role of RAGE-NFκB and Nrf2-antioxidant signaling pathways. J Neurochem 133:700–707CrossRefGoogle Scholar
  2. Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, Wolf PA, Seshadri S (2006) Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham study. Arch Neurol 63:1551–1555CrossRefGoogle Scholar
  3. An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, Chia CW, Egan JM, Ferrucci L, Troncoso J, Levey AI, Lah J, Seyfried NT, Legido-Quigley C, O'Brien R, Thambisetty M (2018) Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement 14:318–329CrossRefGoogle Scholar
  4. Ataie A, Ataee R, Shadifar M, Shahabi S, Aghajanpour SM, Hosseinpour Y (2012) Interaction of memantine with homocysteine on the apoptosis in the rat hippocampus cells. Int J Mol Cell Med 1:145–152Google Scholar
  5. Ávila DL, Araújo GR, Silva M, Miranda PH, Diniz MF, Pedrosa ML, Silva ME, de Lima WG, Costa DC (2013) Vildagliptin ameliorates oxidative stress and pancreatic beta cell destruction in type 1 diabeticrats. Arch Med Res 44:194–202CrossRefGoogle Scholar
  6. Chen S, Liu AR, An FM, Yao WB, Gao XD (2012) Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer’s disease by exendin-4. Age 34:1211–1224CrossRefGoogle Scholar
  7. Choe EY, Cho Y, Choi Y, Yun Y, Wang HJ, Kwon O, Lee BW, Ahn CW, Cha BS, Lee HC, Kang ES (2014) The effect of DPP-4 inhibitors on metabolic parameters in patients with type 2 diabetes. Diabetes Metab J 38:211–219CrossRefGoogle Scholar
  8. Cole SL, Vassar R (2008) The role of amyloid precursor protein processing by BACE1, the beta-secretase, in Alzheimer disease pathophysiology. J Biol Chem 283:29621–29625CrossRefGoogle Scholar
  9. Dai Y, Kamal MA (2014) Fighting Alzheimer’s disease and type 2 diabetes: pathological links and treatment strategies. CNS Neurol Disord Drug Targets 13:271–282CrossRefGoogle Scholar
  10. De Nazareth AM (2017) Type 2 diabetes mellitus in the pathophysiology of Alzheimer’s disease. Dement Neuropsychol 11:105–113CrossRefGoogle Scholar
  11. Deng Y, Wang Z, Wang R, Zhang X, Zhang S, Wu Y, Staufenbiel M, Cai F, Song W (2013) Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis. Eur J Neurosci 37:1962–1969CrossRefGoogle Scholar
  12. Duarte AI, Candeias E, Correia SC, Santos RX, Carvalho C, Cardoso S, Plácido A, Santos MS, Oliveira CR, Moreira PI (2013) Crosstalk between diabetes and brain: glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration. Biochim Biophys Acta 1832:527–541Google Scholar
  13. Ebesunun MO, Obajobi EO (2012) Elevated plasma homocysteine in type 2 diabetes mellitus: a risk factor for cardiovascular diseases. Pan Afr Med J 12:48Google Scholar
  14. Fang FF, Ning Y, Zhanhui F, Xiangqin L, Zheng X, Ming W, Hua H, Yong Y (2013) Alzheimer disease animal model by aluminum, beta-amyloid and transforming growth factor beta-1. J Neurosci 1:15–19Google Scholar
  15. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502Google Scholar
  16. García-Ayllón MS, Small DH, Avila J, Sáez-Valero J (2011) Revisiting the role of acetylcholinesterase in Alzheimer’s disease: cross-talk with P-tau and β-amyloid. Front Mol Neurosci 4:22CrossRefGoogle Scholar
  17. Gupta VB, Laws SM, Villemagne VL, Ames D, Bush AI, Ellis KA, Lui JK, Masters C, Rowe CC, Szoeke C, Taddei K, Martins RN (2011) Plasma apolipoprotein E and Alzheimer disease risk. Neurology 76:1091–1098CrossRefGoogle Scholar
  18. Hayes MR (2012) Neuronal and intracellular signaling pathways mediating GLP-1 energy balance and glycemic effects. Physiol Beha 106:413–416CrossRefGoogle Scholar
  19. Hosseini N, Alaei H, Reisi P, Radahmadi M (2013) The effect of treadmill running on passive avoidance learning in animal model of Alzheimer disease. Int J Prev Med 4:187–192Google Scholar
  20. Huang XT, Li C, Peng XP, Guo J, Yue SJ, Liu W, Zhao FY, Han JZ, Huang YH, Li Y, Cheng QM, Zhou ZG, Chen C, Feng DD, Luo ZQ (2017) An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes. Sci Rep 7:44120CrossRefGoogle Scholar
  21. Johnson JW, Kotermanski SE (2006) Mechanism of action of memantine. Curr Opin Pharmacol 6:61–67CrossRefGoogle Scholar
  22. Kalaria RN, Maestre GE, Arizaga R, Friedland R, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, Prince M, Stewart R, Wimo A, Zhang ZX, Antuono P (2008) Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol 7:812–826CrossRefGoogle Scholar
  23. Khalid I, Fei L, Cheng-Xin G, Alejandra-del CA, Grundke-I I (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118:53–69CrossRefGoogle Scholar
  24. Kim B, Backus C, Oh S, Feldman EL (2013) Hyperglycemia-induced tau cleavage in vitro and in vivo: a possible link between diabetes and Alzheimer’s disease. J Alzheimers Dis 34:727–739CrossRefGoogle Scholar
  25. Kosaraju J, Murthy V, Khatwal RB, Dubala A, Chinni S, Basavan D (2013) Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer’s disease. J Pharm Pharmacol 65:1773–17784CrossRefGoogle Scholar
  26. Lahiri DK, Chen D, Alley GM, Banerjee PK (2006) Effects of memantine on the activity of secretase enzymes in human neuroblastoma cells. Alzheimers Dement 16:S483–S484Google Scholar
  27. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Sarmiento J, Troncoso J, Jackson GR, Kayed R (2012) Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease. FASEB J 26:1946–1959CrossRefGoogle Scholar
  28. Lesne S, Ali C, Gabriel C, Croci N, MacKenzie ET, Glabe CG, Plotkine M, Marchand-Verrecchia C, Vivien D, Buisson A (2005) NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J Neurosci 25:9367–9377CrossRefGoogle Scholar
  29. Li L, Sengupta A, Haque N, Grundke-Iqbal I, Iqbal K (2004) Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration. FEBS Lett 566:261–269CrossRefGoogle Scholar
  30. Li L, Zhang ZF, Holscher C, Gao C, Jiang YH, Liu YZ (2012) Glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains. Eur J Pharmacol 674:280–286CrossRefGoogle Scholar
  31. Linnemann AK, Neuman JC, Battiola TJ, Wisinski JA, Kimple ME, Davis DB (2015) Glucagon-like peptide-1 regulates cholecystokinin production in β-cells to protect from apoptosis. Mol Endocrinol 29:978–987CrossRefGoogle Scholar
  32. Mathieu C, Degrande E (2008) Vildagliptin: a new oral treatment for type 2 diabetes mellitus. Vasc Health Risk Manag 4:1349–1360CrossRefGoogle Scholar
  33. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefGoogle Scholar
  34. Mehanna ET, Barakat BM, ElSayed MH, Tawfik MK (2018) An optimized dose of raspberry ketones controls hyperlipidemia and insulin resistance in male obese rats: effect on adipose tissue expression of adipocytokines and Aquaporin 7. Eur J Pharmacol 832:81–89CrossRefGoogle Scholar
  35. Minkeviciene R, Banerjee P, Tanila H (2004) Memantine improves spatial learning in a transgenic mouse model of Alzheimer’s disease. Pharmacol Exp 311:677–682CrossRefGoogle Scholar
  36. National Research Council (US) (2011) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals, 8th edn. National Academies Press (US), WashingtonGoogle Scholar
  37. Norgaard ML, Andersen SS, Schramm TK, Folke F, Jørgensen CH, Hansen ML, Andersson C, Bretler DM, Vaag A, Køber L, Torp-Pedersen C, Gislason GH (2010) Changes in short- and long-term cardiovascular risk of incident diabetes and incident myocardial infarction—a nationwide study. Diabetologia 53:1612–1619CrossRefGoogle Scholar
  38. Palotás M, Palotás A, Bjelik A, Pákáski M, Hugyecz M, Janka Z, Kálmán J (2005) Effect of general anesthetics on amyloid precursor protein and mRNA levels in the rat brain. Neurochem Res 30:1021–1026CrossRefGoogle Scholar
  39. Pan CY, Wang XL (2013) Profile of vildagliptin in type 2 diabetes: efficacy, safety, and patient acceptability. Ther Clin Risk Manag 9:247–257CrossRefGoogle Scholar
  40. Reno C, Angela M, Yiguo S, Ylva B, Raymond A (2012) Activation of neuronal NMDA receptors induces superoxide-mediated oxidative stress in neighboring neurons and astrocytes. J Neurosci 32:12973–12978CrossRefGoogle Scholar
  41. Riddell DR, Zhou H, Atchison K, Warwick HK, Atkinson PJ, Jefferson J, Xu L, Aschmies S, Kirksey Y, Hu Y, Wagner E, Parratt A, Xu J, Li Z, Zaleska MM, Jacobsen JS, Pangalos MN, Reinhart PH (2008) Impact of apolipoprotein E, apoE polymorphism on brain apoE levels. J Neurosci 28:11445–11453CrossRefGoogle Scholar
  42. Robinson DM, Keating GM (2006) Memantine: a review of its use in Alzheimer’s disease. Drugs 66:1515–1534CrossRefGoogle Scholar
  43. Saura CA, Cardinaux JR (2017) Emerging roles of CREB-regulated transcription coactivators in brain physiology and pathology. J Trends Neurosci 40:720–733CrossRefGoogle Scholar
  44. Takeda S, Sato N, Rakugi H, Morishita R (2011) Molecular mechanisms linking diabetes mellitus and Alzheimer disease: beta-amyloid peptide, insulin signaling, and neuronal function. Mol BioSyst 6:1822–1827CrossRefGoogle Scholar
  45. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858CrossRefGoogle Scholar
  46. Wu Y, Ouyang JP, Wu K, Wang SS, Wen CY, Xia ZY (2005) Rosiglitazone ameliorates abnormal expression and activity of protein tyrosine phosphate 1B in the skeletal muscle of fat-fed, streptozotocin-treated diabetic rats. Aust J Pharm 146:234–243Google Scholar
  47. Yamada N, Araki H, Yoshimura H (2011) Identification of antidepressant-like ingredients in ginseng root (Panax ginseng C.A. Meyer) using a menopausal depressive-like state in female mice: participation of 5-HT2A receptors. Psychopharmacology 216:589–599CrossRefGoogle Scholar
  48. Zhang M, Lv XY, Li J, Xu ZG, Chen L (2008) The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diabetes Res 2008:704045CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Samar S. Khalaf
    • 1
    Email author
  • Mohamed M. Hafez
    • 2
  • Eman T. Mehanna
    • 1
  • Noha M. Mesbah
    • 1
  • Dina M. Abo-Elmatty
    • 1
  1. 1.Department of Biochemistry, Faculty of PharmacySuez Canal UniversityIsmailiaEgypt
  2. 2.Department of Biochemistry, Faculty of PharmacyAhram Canadian University6th of OctoberEgypt

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