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Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

Nuruddin S, Syverstad GH, Lillehaug S, Leergaard TB, Nilsson LN, Ropstad E, Krogenæs A, Haraldsen IR, Torp R - PLoS ONE (2014)

Bottom Line: Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus.Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression.The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.

View Article: PubMed Central - PubMed

Affiliation: Norwegian School of Veterinary Science, Oslo, Norway.

ABSTRACT
Research on Alzheimer's disease (AD) has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG) axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh) and its receptor (Gnrhr) were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate). The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP) mutations (tgArcSwe). At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.

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Estradiol (E2) and testosterone analyses in serum.Hormonal analyses of estradiol (E2) and testosterone show a decline in estradiol and testosterone levels both in males and females, after treatment with Leuprorelin acetate. Significant results are indicated with asterisk (**p<0.01, ***p<0.001). Tot-U - Total (females and males) untreated, Tot-T – Total treated, M-U – Males untreated, M-T – Males treated, F-U – Females untreated, F-T – Females treated.
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pone-0103607-g001: Estradiol (E2) and testosterone analyses in serum.Hormonal analyses of estradiol (E2) and testosterone show a decline in estradiol and testosterone levels both in males and females, after treatment with Leuprorelin acetate. Significant results are indicated with asterisk (**p<0.01, ***p<0.001). Tot-U - Total (females and males) untreated, Tot-T – Total treated, M-U – Males untreated, M-T – Males treated, F-U – Females untreated, F-T – Females treated.

Mentions: The blood samples were also analyzed for testosterone levels. It showed that all treated animals had serum levels of testosterone less than 0.5 nmol/l (p<0.05). The results are presented in Figure 1.


Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

Nuruddin S, Syverstad GH, Lillehaug S, Leergaard TB, Nilsson LN, Ropstad E, Krogenæs A, Haraldsen IR, Torp R - PLoS ONE (2014)

Estradiol (E2) and testosterone analyses in serum.Hormonal analyses of estradiol (E2) and testosterone show a decline in estradiol and testosterone levels both in males and females, after treatment with Leuprorelin acetate. Significant results are indicated with asterisk (**p<0.01, ***p<0.001). Tot-U - Total (females and males) untreated, Tot-T – Total treated, M-U – Males untreated, M-T – Males treated, F-U – Females untreated, F-T – Females treated.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4121068&req=5

pone-0103607-g001: Estradiol (E2) and testosterone analyses in serum.Hormonal analyses of estradiol (E2) and testosterone show a decline in estradiol and testosterone levels both in males and females, after treatment with Leuprorelin acetate. Significant results are indicated with asterisk (**p<0.01, ***p<0.001). Tot-U - Total (females and males) untreated, Tot-T – Total treated, M-U – Males untreated, M-T – Males treated, F-U – Females untreated, F-T – Females treated.
Mentions: The blood samples were also analyzed for testosterone levels. It showed that all treated animals had serum levels of testosterone less than 0.5 nmol/l (p<0.05). The results are presented in Figure 1.

Bottom Line: Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus.Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression.The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.

View Article: PubMed Central - PubMed

Affiliation: Norwegian School of Veterinary Science, Oslo, Norway.

ABSTRACT
Research on Alzheimer's disease (AD) has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG) axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh) and its receptor (Gnrhr) were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate). The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP) mutations (tgArcSwe). At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.

Show MeSH
Related in: MedlinePlus