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Effects of dihydrotestosterone on synaptic plasticity of the hippocampus in mild cognitive impairment male SAMP8 mice

View Article: PubMed Central - PubMed

ABSTRACT

The current study focused on how dihydrotestosterone (DHT) regulates synaptic plasticity in the hippocampus of mild cognitive impairment male senescence-accelerated mouse prone 8 (SAMP8) mice. Five-month-old SAMP8 mice were divided into the control, castrated and castrated-DHT groups, in which the mice were castrated and treated with physiological doses of DHT for a period of 2 months. To determine the regulatory mechanisms of DHT in the cognitive capacity, the effects of DHT on the morphology of the synapse and the expression of synaptic marker proteins in the hippocampus were investigated using immunohistochemistry, qPCR and western blot analysis. The results showed that the expression of cAMP-response element binding protein (CREB), postsynaptic density protein 95 (PSD95), synaptophysin (SYN) and developmentally regulated brain protein (Drebrin) was reduced in the castrated group compared to the control group. However, DHT promoted the expression of CREB, PSD95, SYN and Drebrin in the hippocampus of the castrated-DHT group. Thus, androgen depletion impaired the synaptic plasticity in the hippocampus of SAMP8 and accelerated the development of Alzheimer's disease (AD)-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, DHT regulated synaptic plasticity in the hippocampus of mild cognitive impairment (MCI) SAMP8 mice and delayed the progression of disease to Alzheimer's dementia. In conclusion, androgen-based hormone therapy is a potentially useful strategy for preventing the progression of MCI in aging men. Androgens enhance synaptic markers (SYN, PSD95, and Drebrin), activate CREB, modulate the fundamental biology of synaptic structure, and lead to the structural changes of plasticity in the hippocampus, all of which result in improved cognitive function.

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Immunohistochemical staining shows the effects of castration and DHT intervention on the conversion from MCI to Alzheimer's dementia in SAMP8 mice. Immunohistochemical staining detected (A-C) SYN, (D-F) PSD95, (G-I) Drebrin and (J-K) CREB protein expression in the (A, D, G and J) castration, (B, E, H and K) DHT and (C, F, I and L) P8 groups. A statistical graph showing the difference of protein expression in the (M) four groups. The results are presented as the mean ± standard deviation (n=5). Statistical analysis was performed using one-way ANOVA with LSD post-hoc test. **P<0.01. DHT, dihydrotestosterone; MCI, mild cognitive impairment; SAMP8, senescence-accelerated mouse prone 8; SYN, synaptophysin; PSD95, postsynaptic density protein 95; CREB, cAMP-response element binding protein; Drebrin, developmentally regulated brain protein.
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f1-etm-0-0-3470: Immunohistochemical staining shows the effects of castration and DHT intervention on the conversion from MCI to Alzheimer's dementia in SAMP8 mice. Immunohistochemical staining detected (A-C) SYN, (D-F) PSD95, (G-I) Drebrin and (J-K) CREB protein expression in the (A, D, G and J) castration, (B, E, H and K) DHT and (C, F, I and L) P8 groups. A statistical graph showing the difference of protein expression in the (M) four groups. The results are presented as the mean ± standard deviation (n=5). Statistical analysis was performed using one-way ANOVA with LSD post-hoc test. **P<0.01. DHT, dihydrotestosterone; MCI, mild cognitive impairment; SAMP8, senescence-accelerated mouse prone 8; SYN, synaptophysin; PSD95, postsynaptic density protein 95; CREB, cAMP-response element binding protein; Drebrin, developmentally regulated brain protein.

Mentions: Immunohistochemical staining showed that the positive products of CREB protein were mainly distributed in the neuronal membrane, cytoplasm and projections. Compared with the castration group, the staining in projections of the P8 and DHT groups was dense and thick, and the cytoplasmic membrane immunoreactive substance increased significantly (Fig. 1A-C). The OD value of the castration group was 0.135±0.025, which was significantly lower than that of the P8 group value of 0.270±0.046 (P<0.01). The OD value of DHT group was 0.216±0.034 and was significantly increased compared to the Castration group (P<0.01).


Effects of dihydrotestosterone on synaptic plasticity of the hippocampus in mild cognitive impairment male SAMP8 mice
Immunohistochemical staining shows the effects of castration and DHT intervention on the conversion from MCI to Alzheimer's dementia in SAMP8 mice. Immunohistochemical staining detected (A-C) SYN, (D-F) PSD95, (G-I) Drebrin and (J-K) CREB protein expression in the (A, D, G and J) castration, (B, E, H and K) DHT and (C, F, I and L) P8 groups. A statistical graph showing the difference of protein expression in the (M) four groups. The results are presented as the mean ± standard deviation (n=5). Statistical analysis was performed using one-way ANOVA with LSD post-hoc test. **P<0.01. DHT, dihydrotestosterone; MCI, mild cognitive impairment; SAMP8, senescence-accelerated mouse prone 8; SYN, synaptophysin; PSD95, postsynaptic density protein 95; CREB, cAMP-response element binding protein; Drebrin, developmentally regulated brain protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997989&req=5

f1-etm-0-0-3470: Immunohistochemical staining shows the effects of castration and DHT intervention on the conversion from MCI to Alzheimer's dementia in SAMP8 mice. Immunohistochemical staining detected (A-C) SYN, (D-F) PSD95, (G-I) Drebrin and (J-K) CREB protein expression in the (A, D, G and J) castration, (B, E, H and K) DHT and (C, F, I and L) P8 groups. A statistical graph showing the difference of protein expression in the (M) four groups. The results are presented as the mean ± standard deviation (n=5). Statistical analysis was performed using one-way ANOVA with LSD post-hoc test. **P<0.01. DHT, dihydrotestosterone; MCI, mild cognitive impairment; SAMP8, senescence-accelerated mouse prone 8; SYN, synaptophysin; PSD95, postsynaptic density protein 95; CREB, cAMP-response element binding protein; Drebrin, developmentally regulated brain protein.
Mentions: Immunohistochemical staining showed that the positive products of CREB protein were mainly distributed in the neuronal membrane, cytoplasm and projections. Compared with the castration group, the staining in projections of the P8 and DHT groups was dense and thick, and the cytoplasmic membrane immunoreactive substance increased significantly (Fig. 1A-C). The OD value of the castration group was 0.135±0.025, which was significantly lower than that of the P8 group value of 0.270±0.046 (P<0.01). The OD value of DHT group was 0.216±0.034 and was significantly increased compared to the Castration group (P<0.01).

View Article: PubMed Central - PubMed

ABSTRACT

The current study focused on how dihydrotestosterone (DHT) regulates synaptic plasticity in the hippocampus of mild cognitive impairment male senescence-accelerated mouse prone 8 (SAMP8) mice. Five-month-old SAMP8 mice were divided into the control, castrated and castrated-DHT groups, in which the mice were castrated and treated with physiological doses of DHT for a period of 2 months. To determine the regulatory mechanisms of DHT in the cognitive capacity, the effects of DHT on the morphology of the synapse and the expression of synaptic marker proteins in the hippocampus were investigated using immunohistochemistry, qPCR and western blot analysis. The results showed that the expression of cAMP-response element binding protein (CREB), postsynaptic density protein 95 (PSD95), synaptophysin (SYN) and developmentally regulated brain protein (Drebrin) was reduced in the castrated group compared to the control group. However, DHT promoted the expression of CREB, PSD95, SYN and Drebrin in the hippocampus of the castrated-DHT group. Thus, androgen depletion impaired the synaptic plasticity in the hippocampus of SAMP8 and accelerated the development of Alzheimer's disease (AD)-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, DHT regulated synaptic plasticity in the hippocampus of mild cognitive impairment (MCI) SAMP8 mice and delayed the progression of disease to Alzheimer's dementia. In conclusion, androgen-based hormone therapy is a potentially useful strategy for preventing the progression of MCI in aging men. Androgens enhance synaptic markers (SYN, PSD95, and Drebrin), activate CREB, modulate the fundamental biology of synaptic structure, and lead to the structural changes of plasticity in the hippocampus, all of which result in improved cognitive function.

No MeSH data available.


Related in: MedlinePlus