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. 2019 Apr;14(4):649-657.
doi: 10.4103/1673-5374.245477.

Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer's disease

Xu-Sheng Yan  1 , Zhan-Jun Yang  1 , Jian-Xin Jia  1 , Wei Song  1 , Xin Fang  1 , Zhi-Ping Cai  1 , Dong-Sheng Huo  1 , He Wang  2
Affiliations

Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer's disease

Xu-Sheng Yan et al. Neural Regen Res. 2019 Apr.

Abstract

Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1-42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.

Keywords: Alzheimer's disease; Morris water maze; amyloid beta 1-42; androgen receptor; cognitive dysfunction; flutamide; free radicals; nerve regeneration; neural regeneration; neurodegenerative change; postsynaptic density protein 95; synaptic plasticity; testosterone.

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Conflict of interest statement

None

Figures

Figure 1
Figure 1
Effects of testosterone on cognitive functions of AD rat models in positioning navigation of the Morris water maze test. (A) Escape latency is given in seconds and (B) path length in meters. Data are expressed as the mean (n = 10; one-way analysis of variance followed by the least significant difference post hoc test). *P < 0.05, vs. AD group. AD: AD group; T: testosterone group; F: flutamide group; F + T: flutamide + testosterone group. AD: Alzheimer’s disease.
Figure 2
Figure 2
Effects of testosterone on cognitive functions of AD rat models in probe trials of the Morris water maze test. (A, B) Data are presented as (A) percentage time spent in the target quadrant and (B) number of platform crossings in the probe trials. Data are expressed as the mean ± SD (n = 10; one-way analysis of variance followed by the least significant difference post hoc test). *P < 0.05, vs. AD group. AD: AD group; T: testosterone group; F: flutamide group; F + T: flutamide + testosterone group. AD: Alzheimer’s disease.
Figure 3
Figure 3
Nissl staining to investigate the number of intact pyramidal cells in different groups. (A–D) Alzheimer’s disease, testosterone, flutamide, and flutamide + testosterone groups, respectively. Administration of testosterone elevated the number of intact hippocampal pyramidal cells. Administration of flutamide combined with testosterone resulted in a marked decrease in the number of intact hippocampal pyramidal cells compared with testosterone alone. The number of intact pyramidal cells (arrows; per 1 mm linear length of the same section of the hippocampal CA1 region) was counted under an optical microscope (original magnification, 100×; scale bar: 40 μm).
Figure 4
Figure 4
Golgi staining of dendritic spines from secondary and tertiary apical dendrites of the hippocampal CA1 region in different groups. (A–D) Alzheimer’s disease, testosterone, flutamide, and flutamide + testosterone groups, respectively. Treatment with testosterone increased the dendritic spine density in the hippocampal CA1 region compared with the AD group. Concurrent treatment with testosterone and flutamide decreased dendritic spine density. Dendritic spines (arrows) in different groups were observed under an optical microscope (original magnification, 100×; scale bars: 40 μm).
Figure 5
Figure 5
Immunohistochemical staining of postsynaptic density protein 95 (PSD-95) in the rat hippocampus of different groups. (A–D) Alzheimer’s disease, testosterone, flutamide, and flutamide + testosterone groups, respectively. Testosterone increased the number of PSD-95-positive cells compared with the AD group. Flutamide inhibited the effect of testosterone on PSD-95-stained cells. PSD-95 expression (arrows) was observed using an optical microscope (original magnification, 100×; scale bar: 40 μm).
Figure 6
Figure 6
Western blot assay of relative PSD-95 protein expression levels in the rat hippocampus of different groups. Compared with the AD group, testosterone significantly increased PSD-95 expression levels. When flutamide and testosterone were administered concurrently, the effect of testosterone on PSD-95 expression was inhibited. Expression levels are given as the ratio of PSD-95/GAPDH. Data are expressed as the mean ± SD (n = 15; one-way analysis of variance followed by the least significant difference post hoc test). The experiment was performed in triplicate. *P < 0.05, vs. AD group. AD: AD group; T: testosterone group; F: flutamide group; F + T: flutamide + testosterone group; AD: Alzheimer’s disease; GAPDH: glyceraldehyde phosphate dehydrogenase; PSD-95: postsynaptic density protein 95.
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