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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

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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.

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Abbreviations

AChE:

Acetylcholinestrases

AD:

Alzheimer disease

AGE:

Advanced glycation end products

APO E:

Apolipopreotein E

APP:

Amyloid precursor protein

Aβ:

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

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt

    Samar S. Khalaf, Eman T. Mehanna, Noha M. Mesbah & Dina M. Abo-Elmatty

  2. Department of Biochemistry, Faculty of Pharmacy, Ahram Canadian University, 6th of October, Egypt

    Mohamed M. Hafez

Authors
  1. Samar S. Khalaf
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  2. Mohamed M. Hafez
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  3. Eman T. Mehanna
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  4. Noha M. Mesbah
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  5. Dina M. Abo-Elmatty
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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.

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Correspondence to Samar S. Khalaf.

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

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The authors declare that they have no conflict of interest.

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Khalaf, S.S., Hafez, M.M., Mehanna, E.T. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 392, 685–695 (2019). https://doi.org/10.1007/s00210-019-01616-3

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  • DOI: https://doi.org/10.1007/s00210-019-01616-3

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