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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

Abstract

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.

Keywords

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

Abbreviations

AChE

Acetylcholinestrases

AD

Alzheimer disease

AGE

Advanced glycation end products

APO E

Apolipopreotein E

APP

Amyloid precursor protein

Amyloid beta peptide

BACE 1

β-site Aβ precursorprotein-cleaving enzyme 1

BG

Blood glucose

CNS

Central nervous system

DPP-4

Dipeptidyl peptidase-4

GIP

Glucose-dependent insolinotropic polypeptide

GLP-1

Glucagon-like peptide-1

GLUT3

Glucose transport protein 3

GSK-3β

Glycogen synthase kinase-3 beta

Hcy

Homocysteine

HDL-C

High-density lipoprotein

LDL-C

Low-density lipoprotein cholesterol

LPO

Lipid peroxidation

MDA

Malanodialdhyde

NF-Κβ

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

NMDA

N-methyl-d-aspartate

PBS

Phosphate-buffered saline

PHF

Phospho tau antibody

Pp-2A

Phosphoseryl/phosphothreonyl protein phosphatase-2A

ROS

Reactive oxygen species

STZ

Streptozotocin

T2DM

Type 2diabetes mellitus

TAG

Triacylglycerol

TC

Total cholesterol

TGF-β1

Transforming growth factor beta-1

Notes

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.

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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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