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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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mRNA expression levels across the groups at 4 and 12 months.Hippocampal expression of Gnrh and Gnrhr transcripts in male and female tgArcSwe mice related to control groups. Data are represented as fold change (FC) and standard error mean (SEM). The fold change values are derived from relative quantification and normalization to the expression of two reference genes (B2m and Gusb). Genes with values higher than 1 indicate increased mRNA expression, values lower than 1 decreased mRNA expression in target group relative to control group. Light grey bars demonstrate the fold change value of gene expression in 4 months old tgArcSwe relative to age-matched WT-mice; Grey bars demonstrate the fold change value of gene expression level in 12 months old tgArcSwe relative to age-matched WT-mice. Black bars demonstrate the fold change values of gene expression in 12 months old Gnrh-a treated tgArcSwe relative to vehicle treated tgArcSwe. Both sexes are presented separately. Significant (Wilcoxon signed rank test, p<0.05) changes in gene expression are indicated by asterisks.
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pone-0103607-g002: mRNA expression levels across the groups at 4 and 12 months.Hippocampal expression of Gnrh and Gnrhr transcripts in male and female tgArcSwe mice related to control groups. Data are represented as fold change (FC) and standard error mean (SEM). The fold change values are derived from relative quantification and normalization to the expression of two reference genes (B2m and Gusb). Genes with values higher than 1 indicate increased mRNA expression, values lower than 1 decreased mRNA expression in target group relative to control group. Light grey bars demonstrate the fold change value of gene expression in 4 months old tgArcSwe relative to age-matched WT-mice; Grey bars demonstrate the fold change value of gene expression level in 12 months old tgArcSwe relative to age-matched WT-mice. Black bars demonstrate the fold change values of gene expression in 12 months old Gnrh-a treated tgArcSwe relative to vehicle treated tgArcSwe. Both sexes are presented separately. Significant (Wilcoxon signed rank test, p<0.05) changes in gene expression are indicated by asterisks.

Mentions: To investigate the association between Gnrh/Gnrhr and AD we assessed gene expression levels in hippocampus of tgArcSwe mice at 4 months and 12 months. In addition, we analyzed gene expression level at 12 months after 8 months of treatment with Leuprorelin acetate (25 ng/g). The results are presented in Figure 2. Our gene expression analyses show that at 12 months of age, both Gnrh (p<0.001 in both sexes) and Gnrhr (p<0.01 male and p<0.001 female) mRNA expression were significantly elevated in tgArcSwe compared to age-matched WT in both sexes. Furthermore, gene expression analysis of 4 months old WT mice relative to 12 months old WT mice revealed elevated expression of Gnrh (p<0.05 for male and female) and Gnrhr (p<0.05 for male and female). Strikingly, after 8 months of treatment with Leuprorelin acetate, gene expression of both Gnrh (p<0.001 male and p<0.01 female) and Gnrhr (p<0.001 in both sexes) were down-regulated when Leuprorelin acetate-treated tgArcSwe to vehicle-treated tgArcSwe at the same age were compared. At 4 months no significant differences in Gnrh/Gnrhr were observed. All fold change values, standard errors and p-values are presented in Table 3. The mRNA expression of AβPP was significantly elevated at 4 months in both sexes, consistent with previous findings [27].


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)

mRNA expression levels across the groups at 4 and 12 months.Hippocampal expression of Gnrh and Gnrhr transcripts in male and female tgArcSwe mice related to control groups. Data are represented as fold change (FC) and standard error mean (SEM). The fold change values are derived from relative quantification and normalization to the expression of two reference genes (B2m and Gusb). Genes with values higher than 1 indicate increased mRNA expression, values lower than 1 decreased mRNA expression in target group relative to control group. Light grey bars demonstrate the fold change value of gene expression in 4 months old tgArcSwe relative to age-matched WT-mice; Grey bars demonstrate the fold change value of gene expression level in 12 months old tgArcSwe relative to age-matched WT-mice. Black bars demonstrate the fold change values of gene expression in 12 months old Gnrh-a treated tgArcSwe relative to vehicle treated tgArcSwe. Both sexes are presented separately. Significant (Wilcoxon signed rank test, p<0.05) changes in gene expression are indicated by asterisks.
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Related In: Results  -  Collection

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

pone-0103607-g002: mRNA expression levels across the groups at 4 and 12 months.Hippocampal expression of Gnrh and Gnrhr transcripts in male and female tgArcSwe mice related to control groups. Data are represented as fold change (FC) and standard error mean (SEM). The fold change values are derived from relative quantification and normalization to the expression of two reference genes (B2m and Gusb). Genes with values higher than 1 indicate increased mRNA expression, values lower than 1 decreased mRNA expression in target group relative to control group. Light grey bars demonstrate the fold change value of gene expression in 4 months old tgArcSwe relative to age-matched WT-mice; Grey bars demonstrate the fold change value of gene expression level in 12 months old tgArcSwe relative to age-matched WT-mice. Black bars demonstrate the fold change values of gene expression in 12 months old Gnrh-a treated tgArcSwe relative to vehicle treated tgArcSwe. Both sexes are presented separately. Significant (Wilcoxon signed rank test, p<0.05) changes in gene expression are indicated by asterisks.
Mentions: To investigate the association between Gnrh/Gnrhr and AD we assessed gene expression levels in hippocampus of tgArcSwe mice at 4 months and 12 months. In addition, we analyzed gene expression level at 12 months after 8 months of treatment with Leuprorelin acetate (25 ng/g). The results are presented in Figure 2. Our gene expression analyses show that at 12 months of age, both Gnrh (p<0.001 in both sexes) and Gnrhr (p<0.01 male and p<0.001 female) mRNA expression were significantly elevated in tgArcSwe compared to age-matched WT in both sexes. Furthermore, gene expression analysis of 4 months old WT mice relative to 12 months old WT mice revealed elevated expression of Gnrh (p<0.05 for male and female) and Gnrhr (p<0.05 for male and female). Strikingly, after 8 months of treatment with Leuprorelin acetate, gene expression of both Gnrh (p<0.001 male and p<0.01 female) and Gnrhr (p<0.001 in both sexes) were down-regulated when Leuprorelin acetate-treated tgArcSwe to vehicle-treated tgArcSwe at the same age were compared. At 4 months no significant differences in Gnrh/Gnrhr were observed. All fold change values, standard errors and p-values are presented in Table 3. The mRNA expression of AβPP was significantly elevated at 4 months in both sexes, consistent with previous findings [27].

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