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

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Abstract


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.


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About the authors

Alla V. Stavrovskaya

Research Center of Neurology

Author for correspondence.
Email: stavrovskaya.al@gmail.com
ORCID iD: 0000-0002-8689-0934
SPIN-code: 8013-7362
Scopus Author ID: 8322296500
ResearcherId: C-7098-2012

Russian Federation, 80, Volokolamskoye shosse, Moscow, 125367

PhD in Biology, leading research associate

Dmitry N. Voronkov

Research Center of Neurology

Email: voronkov@neurology.ru
ORCID iD: 0000-0001-5222-5322
SPIN-code: 1576-8871
Scopus Author ID: 23010332800
ResearcherId: B-3910-2012

Russian Federation, 80, Volokolamskoye shosse, Moscow, 125367

PhD, senior researcher

Ekaterina A. Shestakova

Endocrinology Research Centre

Email: katiashestakova@mail.ru
ORCID iD: 0000-0001-6612-6851
SPIN-code: 1124-7600
https://www.endocrincentr.ru/doctors/shestakova-ekaterina-alekseevna

Russian Federation, 11 Dm. Ulyanova str., Moscow, 117036

MD, PhD

Anastasiya S. Gushchina

Research Center of Neurology

Email: anastaisha-2015@mail.ru
ORCID iD: 0000-0003-3026-0279
SPIN-code: 4017-5024
Scopus Author ID: 57200116939

Russian Federation, 80, Volokolamskoye shosse, Moscow, 125367

research associate

Artyom S. Olshansky

Research Center of Neurology

Email: olshansky@neurology.ru
ORCID iD: 0000-0002-5696-8032
SPIN-code: 7072-0721

Russian Federation, 80, Volokolamskoye shosse, Moscow, 125367

PhD in Biology, senior research associate

Nina G. Yamshikova

Research Center of Neurology

Email: nyamshikova@yandex.ru
ORCID iD: 0000-0003-4387-2266
SPIN-code: 9385-5576
Scopus Author ID: 6503897870

Russian Federation, 80, Volokolamskoye shosse, Moscow, 125367

PhD in Biology, leading research associate

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Supplementary files

Supplementary Files Action
1.
Fig. 1. Design of a research.

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2.
Fig. 2. Results of the intraperitoneal glucose tolerance test.

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3.
Fig. 3. Changes in animal body weight.

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4.
Fig. 4. Morphological pattern of pancreas (a-z) and liver (i-m) in animals treated with NCD (a, d, and), in group of CCD LO (b, e, k), group of CCC CTS (c, g, l) and group of CCC CTS (g, z, m): a-g, and red - detection by lip. D-h - pancreatic islets, detection of chromogranin A (green), nuclei of DAPI (blue). Scale: 1 mm - in figures a-g, 250 mcm - in figures d-h, 50 mcm - in figures i-m.

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5.
Fig. 5. Changes in the wall III of the ventricle of the brain and adjacent structures of the hypothalamus under the action of STZ (× 40): a, b - degeneration of GFAP-positive α-tanocytes, damage to the ventricle wall and reduction of astroglia density (GFAP dislocation); C, d is the accumulation of β-amyloid in neurons; Administration of physiological saline (a, c); Intracentricular administration of streptosocin (b, g); The cores are DAPI (blue).

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6.
Fig. 6. Changes in the mediobasal structures of hypothalamus under the action of STZ (× 10): a, b, b - cyclonucleotide phosphatase (CNP); D, e, e is glyofibrillar protein (GFAP); G, h, and are dopamine (TH-positive) neurons of the arcuate nucleus. Symbols: arrows indicate areas of damage; The cores are DAPI (blue).

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7.
Fig. 7. Density of GFAP-positive astrocytes (a) and dopaminergic neurons (b) in the arcuate nucleus of the hypothalamus (M ± SD; ANOVA, posteriory test Tuki).

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Copyright (c) 2020 Stavrovskaya A.V., Voronkov D.N., Shestakova E.A., Gushchina A.S., Olshansky A.S., Yamshikova N.G.

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