Streptozocin-induced Alzheimer’s disease as an independent risk factor for the development of hyperglycemia in Wistar rats

BACKGROUND: In recent years the theme of the relationship of Alzheimer’s disease (AD) and metabolic disorders has been widely discussed. Nevertheless, it remains unclear whether AD is a direct cause of carbohydrate metabolism disorders or it is the presence of classical risk factors for type 2 diabetes mellitus (DM 2), primarily obesity, that significantly increases the risk of AD.

AIM: To evaluate the separate contribution of two factors to the development of disorders of carbohydrate metabolism: (1) weight gain due to a high-calorie diet and (2) experimental-induced AD.

METHODS: Male Wistar rats were injected with streptozocin (STZ) in the lateral ventricles of the brain to induce AD or saline (sham operated animals - SO) during stereotactic operations. After 2 weeks, the animals were divided into four groups: 1) the SO group, which was assigned to the normal calorie (NCD) diet (SO NCD); 2) the SO group, which was assigned to the high-calorie diet (SO HCD); 3) the group to which the norm-calorie diet was prescribed after the administration of STZ into the lateral ventricles of the brain (STZ NCD); 4) the group to which the HCD was assigned after the administration of STZ (STZ HCD). The animals were on a diet for 3 months. Intraperitoneal glucose tolerance tests were carried out before the diet and after 3 months. At the end of the study, a morphological assessment of brain tissue, pancreas, and liver was performed.

RESULTS: 3 months after surgical interventions and the appointment of diets, the glycemic curves significantly differed in the 4 studied groups: normoglycemia persisted only in the SO + NCD group, while HCD and the STZ administration were accompanied by the development of hyperglycemia (p = 0.0001). The STZ + NСD group, which represented the isolated effect of AD, was also characterized by impaired carbohydrate metabolism. A morphological study showed that HCD leads to a more pronounced ectopic accumulation of fat in the liver and pancreas tissue than NCD. The administration of STZ, regardless of the diet, led to changes typical for the AD model – an increase in the size of the ventricles of the brain, degeneration of white matter, and the accumulation of β-amyloid in the hypothalamus.

CONCLUSIONS: The STZ-induced brain damage typical for AD led to impaired carbohydrate metabolism regardless of diet and was an independent risk factor for hyperglycemia.

Alzheimer disease, type 2 diabetes mellitus, hyperglycemia, obesity, streptozocin, hypothalamus, rats

1. Benziger CP, Roth GA, Moran AE. The Global Burden of Disease Study and the Preventable Burden of NCD. Glob Heart. 2016;11(4):393-397. doi: https://doi.org/10.1016/j.gheart.2016.10.024

2. Surkova EV. Diabetes mellitus and the central nervous system. Ther arch. 2016;88(10):82-86. 10.17116/terarkh201688682-86

3. Anjum I, Fayyaz M, Wajid A, et al. Does obesity increase the risk of dementia: a literature review. Cureus. 2018;10(5):e2660. doi: https://doi.org/10.7759/cureus.2660

4. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. London: Academic Press; 2007. 456 p.

5. Goryacheva MA, Makarova MN. Special aspects of glucose tolerance test in small laboratory rodents (mice and rats). Mezhdunarodnii vestnik veterinarii. 2016;3:155-159.

6. Karkishchenko NN. Rukovodstvo po laboratornym zhivotnym i al’ternativnym modeliam v biomeditsinskikh issledovaniyakh. Ed by NN Karkishchenko, SV Grachev. Moscow: Profil’; 2010, 358 p.

7. Schwingshackl L, Hoffmann G, Lampousi AM, et al. Food groups and risk of type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies. Eur J Epidemiol. 2017;32(5):363–375. doi:10.1007/s10654-017-0246-y

8. Janson J, Laedtke T, Parisi JE, et al. Increased risk of type 2 diabetes in alzheimer disease. Diabetes. 2004;53(2):474-481. doi: https://doi.org/10.2337/diabetes.53.2.474

9. Kamat P. Streptozotocin induced Alzheimer′s disease like changes and the underlying neural degeneration and regeneration mechanism. Neural Regen Res. 2015;10(7):1050-1052. doi: https://doi.org/10.4103/1673-5374.160076

10. Gupta S, Yadav K, Mantri SS, et al. Evidence for compromised insulin signaling and neuronal vulnerability in experimental model of sporadic Alzheimer’s disease. Mol Neurobiol. 2018;55(12): 8916−8935. doi: https://doi.org/10.1007/s12035-018-0985-0

11. Deeds MC, Anderson JM, Armstrong AS, et al. Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab Anim. 2011;45(3):131-140. doi: https://doi.org/10.1258/la.2010.010090

12. Srinivasan K, Viswanad B, Asrat L, et al. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005;52(4):313-320. doi: https://doi.org/10.1016/j.phrs.2005.05.004

13. Grieb P. Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer’s Disease: in Search of a Relevant Mechanism. Mol Neurobiol. 2016;53(3):1741−1752. doi: https://doi.org/10.1007/s12035-015-9132-3

14. Bloch K, Gil-Ad I, Vanichkin A, et al. Intracerebroventricular Streptozotocin induces obesity and dementia in Lewis rats. J Alzheimers Dis. 2017;60(1):121-136. doi: https://doi.org/10.3233/JAD-161289

15. Zhang X, van den Pol AN. Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis. Nat Neurosci. 2016;19(10):1341-1347. doi: https://doi.org/10.1038/nn.4372

16. García-Cáceres C, Balland E, Prevot V, et al. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci. 2019;22(1):7-14. doi: https://doi.org/10.1038/s41593-018-0286-y

17. Vercruysse P, Vieau D, Blum D, et al. Hypothalamic alterations in neurodegenerative diseases and their relation to abnormal energy metabolism. Front Mol Neurosci. 2018;11:2. doi:10.3389/fnmol.2018.00002

18. Zheng H, Zhou Q, Du Y, et al. The hypothalamus as the primary brain region of metabolic abnormalities in APP/PS1 transgenic mouse model of Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis. 2018;1864(1):263-273. doi: https://doi.org/10.1016/j.bbadis.2017.10.028

19. Clarke JR, Lyra E Silva NM, Figueiredo CP, et al. Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation. EMBO Mol Med. 2015;7(2):190-210. doi: https://doi.org/10.15252/emmm.201404183

20. Ishii M, Wang G, Racchumi G, et al. Transgenic mice overexpressing amyloid precursor protein exhibit early metabolic deficits and a pathologically low leptin state associated with hypothalamic dysfunction in arcuate neuropeptide neurons. J Neurosci. 2014;34(27):9096-9106. doi: https://doi.org/10.1523/JNEUROSCI.0872-14.2014

21. Verberne AJ, Sabetghadam A, Korim WS. Neural pathways that control the glucose counterregulatory response. Front Neurosci. 2014;8:38. doi: https://doi.org/10.3389/fnins.2014.00038

22. Timper K, Brüning JC. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis Model Mech. 2017;10(6):679-689. doi: https://doi.org/10.1242/dmm.026609

23. Baloyannis SJ, Mavroudis I, Mitilineos D, et al. The hypothalamus in Alzheimer’s disease: a Golgi and electron microscope study. Am J Alzheimers Dis Other Demen. 2015;30(5):478-487. doi: https://doi.org/10.1177/1533317514556876

24. Ishii M, Iadecola C. Metabolic and non-cognitive manifestations of Alzheimer’s disease: the hypothalamus as both culprit and target of pathology. Cell Metab. 2015;22(5):761-776. doi: https://doi.org/10.1016/j.cmet.2015.08.016

25. Bogolepova AN. Alzheimer’’s disease and diabetes mellitus. Meditsinskiy sovet. 2015;18:36-40. doi: 10.21518/2079-701X-2015-18-36-40

26. Tran DQ, Tse EK, Kim MH, Belsham DD. Diet-induced cellular neuroinflammation in the hypothalamus: mechanistic insights from investigation of neurons and microglia. Mol Cell Endocrinol. 2016;438:18-26. doi: https://doi.org/10.1016/j.mce.2016.05.015

27. Guillemot-Legris O, Muccioli GG. Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci. 2017;40(4): 237-253. doi: https://doi.org/10.1016/j.tins.2017.02.005.

28. Rollins CP, Gallino D, Kong V, et al. Contributions of a high-fat diet to Alzheimer’s disease-related decline: a longitudinal behavioural and structural neuroimaging study in mouse models. Neuroimage Clin. 2019;21:101606. doi: https://doi.org/10.1016/j.nicl.2018.11.016

29. Rodriguez-Casado A, Toledano-Díaz A, Toledano A. Defective insulin signalling, mediated by inflammation, connects obesity to Alzheimer disease. Relevant pharmacological therapies and preventive dietary interventions. Curr Alzheimer Res. 2017;14(8):894-911. doi: https://doi.org/10.2174/1567205014666170316161848

30. Shingo AS, Kanabayashi T, Kito S, Murase T. Intracerebroventricular administration of an insulin analogue recovers STZ-induced cognitive decline in rats. Behav Brain Res. 2013;241:105-111. doi: https://doi.org/10.1016/j.bbr.2012.12.005

31. Palleria C, Leo A, Andreozzi F, et al. Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects. Behav Brain Res. 2017;321:157-169. doi: https://doi.org/10.1016/j.bbr.2017.01.004

32. Shestakova EA, Stavrovskaya AV, Gushchina AS, et al. Cognitive function and metabolic features in male Sprague-Dawley rats receiving high-fat and low-calorie diets. Obesity and metabolism. 2018;15(4):65-73. doi: 10.14341/OMET10022

33. Goldman ES, Goez D, Last D, et al. High-fat diet protects the blood-brain barrier in an Alzheimer’s disease mouse model. Aging Cell. 2018;17(5):e12818. doi: https://doi.org/10.1111/acel.12818

34. Lin B, Hasegawa Y, Takane K, et al. High-fat-diet intake enhances cerebral amyloid angiopathy and cognitive impairment in a mouse model of Alzheimer’s disease, independently of metabolic disorders. J Am Heart Assoc. 2016;5(6). pii: e003154. doi: https://doi.org/10.1161/JAHA.115.003154