Hindlimb Unloading Induces Apoptosis and Autophagy but Not Neurodegeneration in the Hippocampus of the Rats

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Abstract

Physical activity is well known to have a beneficial effect on whole body functions, whereas a sedentary lifestyle contributes to the development of metabolic and other diseases and can lead to cognitive decline and increased risk of dementia. The hippocampus mainly controls cognitive performance and the hippocampal neurodegeneration is directly correlated with dementia progression. Hindlimb unloading (HU) is a widely used method to simulate microgravity in rodents and can be used as a model of mobility restriction since one of the main factors of HU is muscle disuse. Additionally, rodents show impaired learning and memory after long-term HU. Here, we explored whether HU would affect the survival or death of the hippocampal cells. Our data demonstrated that after 3-day HU, both apoptosis and autophagy were activated in the hippocampus, as evidenced by the activation of caspase 3 and 9 and an increase in the number of Cathepsin D and LC3b double-positive cells correspondently. Our data indicated that HU has no deleterious effects leading to neurodegeneration for up to 14 days. Moreover, our results also showed that the activation of autophagy during short-term HU had a protective effect, as we did not observe any cell loss or damage.

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About the authors

E. A. Oleynik

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences; Vienna University of Technology (TU Wien)

Email: mglazova@iephb.ru
Russian Federation, Saint Petersburg; Vienna, Austria

A. S. Berezovskaya

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: mglazova@iephb.ru
Russian Federation, Saint Petersburg

A. A. Kulikov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: mglazova@iephb.ru
Russian Federation, Saint Petersburg

S. A. Tyganov

Institute of Biomedical Problems of the Russian Academy of Sciences

Email: mglazova@iephb.ru
Russian Federation, Moscow

A. A. Naumova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: mglazova@iephb.ru
Russian Federation, Saint Petersburg

E. V. Chernigovskaya

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: mglazova@iephb.ru
Russian Federation, Saint Petersburg

B. S. Shenkman

Institute of Biomedical Problems of the Russian Academy of Sciences

Email: mglazova@iephb.ru
Russian Federation, Moscow

M. V. Glazova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Author for correspondence.
Email: mglazova@iephb.ru
Russian Federation, Saint Petersburg

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2. Fig. 1. The number of cells in dentate gyrus and CA3c did not change during the hanging process. The number of cells was counted in the granular layer of dentate gyrus (DG) (a) and in CA3c (b) after 1 (1HU), 3 (3HU), 7 (7HU) and 14 (14HU) days of hanging per 10000 mm2. Data are presented as median ± interquartile range. c, d - representative images of hippocampi of control rats (c) and rats after 7 days of hanging (7HU) stained with methylene blue (d). DG - granular layer of dentate gyrus; CA3c - cells of CA3c field

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3. Fig. 2. Three-day incubation resulted in changes in apoptosis-related proteins. Western blotting revealed a significant increase in the levels of cleaved caspases 3 (cl-casp3) (a) and 9 (cl-casp9) (b) in the hippocampus after 3-day HUVECs. In contrast, Bcl-2 levels were reduced after 3-day incubation (c). Data are presented in conventional units as median ± interquartile range. * - p < 0.05. d - representative immunoblots of cleaved caspases 3 (cl-casp3) and 9 (cl-casp9), Bcl-2 and actin (actin). Bands of 17 and 35 kDa were used to analyse active caspases 3 and 9, respectively

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4. Fig. 3. Autophagy activated in hilus and CA3c after short-term incubation. a, b - Western blot analysis showed decreased expression of beclin-1 (beclin-1, a) and p62 (b) in the hippocampus. c - Representative immunoblots of beclin-1 (beclin-1), p62 and actin (actin). d-e - Estimation of the number of cathepsin D- (cathepsin D, green) and LC3b- (red) positive cells in the hilus (d), CA3c (e) and DG granular layer (DG). Data are presented as mean number of cells per 10000 µm as median ± interquartile range. * - p < 0.05. g, h - representative hippocampal images of control (g) rats and (h) rats after 3-day incubation (3HU). Arrows indicate cathepsin D+LC3b positive cells

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