Skip to main content

Advertisement

SpringerLink
Log in

Investigation of extracellular matrix genes associated with Alzheimer’s disease in the hippocampus of experimental diabetic model rats

  • Original Article
  • Published:
International Journal of Diabetes in Developing Countries Aims and scope Submit manuscript

Abstract

Backround

Both type 2 diabetes (T2D) and Alzheimer’s disease affect large number of people all over the world, especially in developed countries, and involve common molecular mechanisms in degenerative processes.

Aim

Our study is to investigate the expression levels of the ADAMTS4, TIMP3, RELN, and BCAN genes which encode extracellular matrix molecules and are thought to be related to the pathophysiology of Alzheimer’s disease in rats that we used to develop a T2D model by injection of a streptozotocin (STZ) and feeding with high-fat diet (HFD).

Material and methods

In total, 40 rats were divided into four groups: HFD + STZ (10), HFD (10), STZ (10), and the control (10). The weight and blood glucose levels of all rats were recorded, and the insulin tolerance test was performed. At the end of the experimental period, the hippocampus of the rats was isolated and a part of this was used for gene expression analysis through real-time PCR, whereas other parts were used for histological analyses.

Results

Our results show that plaque-like structures were found in the histological examination of the experimental T2D model. In molecular studies, the expression levels of the ADAMTS4, TIMP3, RELN, and BCAN genes were decreased in the HFD +STZ and STZ groups compared with the control, whereas the same expression levels, except that of inhibitor TIMP3, were found to increase in the HFD group.

Conclusion

These genes encoding proteases that regulate neuronal activity have decreased levels in the T2D model. There may be potential in the adoption of new treatment approaches for Alzheimer’s and T2D.

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

Similar content being viewed by others

References

  1. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81.

    Article  CAS  PubMed  Google Scholar 

  2. Ley SH, Meigs JB. Epidemiology and risk factors of type 2 diabetes. Switzerland: Endocrinology; 2018.

    Google Scholar 

  3. Introduction. Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(1):S1–2.

    Google Scholar 

  4. Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2016;39(11):2065–79.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Goldstein BJ, Müller-Wieland D. Type 2 diabetes. 2nd ed. USA: Informa Healthcare; 2008. p. 13–26.

    Google Scholar 

  6. Kyrou I, Tsigos C. Obesity in the elderly diabetic patient: ıs weight loss beneficial? No. Diabetes Care. 2009;32(2):403–9.

    Article  Google Scholar 

  7. Goyal R, Jialal I. Diabetes mellitus type 2. Treasure Island: StatPearls; 2020.

    Google Scholar 

  8. Pulgaron ER, Delamater AM. Obesity and type 2 diabetes in children: epidemiology and treatment. Curr Diab Rep. 2014;14(8):508.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ridge PG, Ebbert MT, Kauwe JS. Genetics of Alzheimer’s disease. Biomed Res Int. 2013;25:254954.

    Google Scholar 

  10. Ciudin A. Diabetes mellitus and Alzheimer’s disease: an unforgettable relation. Endocrinol Nutr. 2016;93(5):191–3.

    Article  Google Scholar 

  11. Cole AR, Astell A, Green C, Sutherland C. Molecular connexions between dementia and diabetes. Neurosci Biobehav Rev. 2007;3:1046–63.

    Article  Google Scholar 

  12. Miyata S, Kitagawa H. Formation and remodeling of the brain extracellular matrix in neural plasticity: roles of chondroitin sulfate and hyaluronan. Biochim Biophys Acta. 2017;1861(10):2420–34.

    Article  CAS  Google Scholar 

  13. Gottschall PE, Howell MD. ADAMTS expression and function in central nervous system injury and disorders. Matrix Biol. 2015;44-46:70–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Morawski M, Filippov M, Tzinia A, Tsilibary E, Vargova L. ECM in brain aging and dementia. Prog Brain Res. 2014;214:207–27.

    Article  PubMed  Google Scholar 

  15. Frischknecht R, Happel MFK. Impact of the extracellular matrix on plasticity in juvenile and adult brains. e-Neuroforum. 2016;7:1–6. https://doi.org/10.1007/s13295-015-0021-z January 13,2021.

    Article  Google Scholar 

  16. Qinna NA, Badwan AA. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats. Drug Des Devel Ther. 2015;9:2515–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pentkowski NS, Litvin Y, Blanchard DC, Vasconcellos A, King LB, Blanchard RJ. Effects of acidic-astressin and ovine-CRF microinfusions into the ventral hippocampus on defensive behaviors in rats. Horm Behav. 2009;56(1):35–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hazman Ö, Ovalı S. Investigation of the anti-ınflammatory effects of safranal on high-fat diet and multiple low-dose streptozotocin ınduced type 2 diabetes rat model. Inflammation. 2015;38(3):1012–9.

    Article  CAS  PubMed  Google Scholar 

  19. Okamoto T, Kanemoto N, Ohbuchi Y, Okano M, Fukui H, Sudo T. Characterization of STZ-ınduced type 2 diabetes in Zucker fatty rats. Exp Anim. 2008;57(4):335–45.

    Article  CAS  PubMed  Google Scholar 

  20. Sandhir R, Gupta S. Molecular and biochemical trajectories from diabetes to Alzheimer’s disease: a critical appraisal. World J Diabetes. 2015;6(12):1223–42.

    Article  PubMed  PubMed Central  Google Scholar 

  21. De la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes evidence reviewed. J Diabetes Sci Technol. 2008;2:1101–13.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mittal K. Katare DP Shared links between type 2 diabetes mellitus and Alzheimer’s disease: a review. Diabetol Metab Syndr. 2016;10(2):144–9.

    Article  Google Scholar 

  23. Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta. 2017;1863(5):1037–45.

    Article  Google Scholar 

  24. Biessels GJ, Kappelle LJ. Increased risk of Alzheimer’s disease in type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem Soc Trans. 2005;33(5):1041–4.

    Article  CAS  PubMed  Google Scholar 

  25. Lemarchant S, Pruvost M, Montaner J, Emery E, Vivien D, Kanninen K, et al. ADAMTS proteoglycanases in the physiological and pathological central nervous system. J Neuroinflammation. 2013;10:133.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Satoh K, Suzuki N, Yokota H. ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs) is transcriptionally induced in beta-amyloid treated rat astrocytes. Neurosci Lett. 2000;289:177–80.

    Article  CAS  PubMed  Google Scholar 

  27. Gurses MS, Ural MN, Gulec MA, Akyol O, Akyol S. Pathophysiological function of ADAMTS enzymes on molecular mechanism of Alzheimer’s disease. Aging Dis. 2016;7(4):479–90.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lemarchant S, Pomeshchik Y, Kidin I, Kärkkäinen V, Valonen P, Lehtonen S, et al. ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis. Mol Neurodegener. 2016;11:10.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Pehlivan S, Fedakar R, Eren B, Akyol S, Eren F, Turkmen Inanır N, et al. ADAMTS4, 5, 9, and 15 expressions in the autopsied brain of patients with Alzheimers disease: a preliminary immünohistochemistry study. Bull Clin Psychopharmacol. 2016;26(1):7–14.

    Article  CAS  Google Scholar 

  30. Gibb SL, Zhao Y, Potter D, Hylin MJ, Bruhn R, Baimukanova G, et al. TIMP3 attenuates the loss of neural stem cells, mature neurons and neurocognitive dysfunction in traumatic brain ınjury. Stem Cells. 2015;33(12):3530–44.

    Article  CAS  PubMed  Google Scholar 

  31. Yu NN, Tan MS, Yu JT, Xie AM, Tan L. The role of reelin signaling in Alzheimer’s disease. Mol Neurobiol. 2016;53(8):5692–700.

    Article  CAS  PubMed  Google Scholar 

  32. Krstic D, Rodriguez M, Knuesel I. Regulated proteolytic processing of reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators. PLoS One. 2012;7(10):47793.

    Article  Google Scholar 

  33. Saez-Valero J, Costell M, Sjogren M, Andreasen N, Blennow K. Luque JM Altered levels of cerebrospinal fluid reelin in frontotemporal dementia and Alzheimer’s disease. J Neurosci Res. 2003;72(1):132–6.

    Article  CAS  PubMed  Google Scholar 

  34. Gary SC, Zerillo CA, Chiang VL, Gaw JU, Gray G, Hockfield S. cDNA cloning, chromosomal localization, and expression analysis of human BEHAB/brevican, a brain specific proteoglycan regulated during cortical development and in glioma. Gene. 2000;256(1-2):139–47.

    Article  CAS  PubMed  Google Scholar 

  35. Valenzuela JC, Heise C, Franken G, Singh J, Schweitzer B, Seidenbecher CI, et al. Hyaluronanbased extracellular matrix under conditions of homeostatic plasticity. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1654):20130606.

    Article  Google Scholar 

  36. Morawski M, Brückner G, Jäger C, Seeger G, Matthews RT, Arendt T. Involvement of perineuronal and perisynaptic extracellular matrix in Alzheimer’s disease neuropathology. Brain Pathol. 2012;22(4):547–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by “Cukurova University Research Projects Funding Unit” with project number 2016-5883.

Author information

Authors and Affiliations

  1. Department of Medical Biology, School of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey

    Lütfiye Özpak

  2. Department of Medical Biology, School of Medicine, Çukurova University, Adana, Turkey

    Ayfer Pazarbasi & M. Bertan Yılmaz

  3. Department of Biophysics, School of Medicine, Çukurova University, Adana, Turkey

    Işıl Öcal

  4. Department of Biostatistics, School of Medicine, Çukurova University, Adana, Turkey

    Hülya Binokay

Authors
  1. Lütfiye Özpak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayfer Pazarbasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Işıl Öcal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Bertan Yılmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hülya Binokay
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Lütfiye Özpak, Ayfer Pazarbasi, Işıl Öcal, M. Bertan Yılmaz, and Hülya Binokay. The first draft of the manuscript was written by Lütfiye Özpak and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lütfiye Özpak.

Ethics declarations

Conflict of interest

Throughout the study, all interventions applied to the animals were carried out in accordance with the approval (reference number: ÇÜTF-DETAUM-09; date: 27.11.2015) of Çukurova University Animal Experiments Local Ethics Committee.

Conflict of interest

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Özpak, L., Pazarbasi, A., Öcal, I. et al. Investigation of extracellular matrix genes associated with Alzheimer’s disease in the hippocampus of experimental diabetic model rats. Int J Diabetes Dev Ctries 42, 82–90 (2022). https://doi.org/10.1007/s13410-021-00951-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13410-021-00951-7

Keywords

Search

Navigation