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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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Related in: MedlinePlus

Immunohistochemistry for Aβ-deposits in the male and female mouse brain.Immunohistochemistry for amyloid (Aβx-40) in the right hemisphere of male and female mouse brain. Aβ-deposits are found throughout the cerebral cortex (Cx) and hippocampus (Hc) in all animals regardless of treatment. Enlarged images E–H show morphological details in the hippocampus. Insets show sections from wild-type animals of corresponding genders demonstrating that background staining was low.
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pone-0103607-g003: Immunohistochemistry for Aβ-deposits in the male and female mouse brain.Immunohistochemistry for amyloid (Aβx-40) in the right hemisphere of male and female mouse brain. Aβ-deposits are found throughout the cerebral cortex (Cx) and hippocampus (Hc) in all animals regardless of treatment. Enlarged images E–H show morphological details in the hippocampus. Insets show sections from wild-type animals of corresponding genders demonstrating that background staining was low.

Mentions: The amount of Aβx-40 labeling was determined by quantitative image analysis. Depositions of amyloid-beta (Aβ) loads in cerebral cortex, hippocampus and thalamus of 12 months old tgArcSwe mice are shown in Figure 3. The average plaque load in the hippocampus of 12 months old female and male tgArcSwe mice receiving Leuprorelin acetate (7 female and 3 male mice), did not differ significantly when compared to untreated sex- and age-matched tgArcSwe mice (4 female and 6 male mice), (Figure 4). However, we found a trend indicating a lower plaque load in the cerebral cortex of drug treated females (p = 0.06) compared to vehicle-treated females. Comparisons of plaque load in cerebral cortex and thalamus in the same animal groups did not reveal any differences. Our conclusions are mostly based on the female group as the group of treated male mice was reduced due to an inadvertent loss of animals, although the results among the male mice pointed in the same direction.


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)

Immunohistochemistry for Aβ-deposits in the male and female mouse brain.Immunohistochemistry for amyloid (Aβx-40) in the right hemisphere of male and female mouse brain. Aβ-deposits are found throughout the cerebral cortex (Cx) and hippocampus (Hc) in all animals regardless of treatment. Enlarged images E–H show morphological details in the hippocampus. Insets show sections from wild-type animals of corresponding genders demonstrating that background staining was low.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103607-g003: Immunohistochemistry for Aβ-deposits in the male and female mouse brain.Immunohistochemistry for amyloid (Aβx-40) in the right hemisphere of male and female mouse brain. Aβ-deposits are found throughout the cerebral cortex (Cx) and hippocampus (Hc) in all animals regardless of treatment. Enlarged images E–H show morphological details in the hippocampus. Insets show sections from wild-type animals of corresponding genders demonstrating that background staining was low.
Mentions: The amount of Aβx-40 labeling was determined by quantitative image analysis. Depositions of amyloid-beta (Aβ) loads in cerebral cortex, hippocampus and thalamus of 12 months old tgArcSwe mice are shown in Figure 3. The average plaque load in the hippocampus of 12 months old female and male tgArcSwe mice receiving Leuprorelin acetate (7 female and 3 male mice), did not differ significantly when compared to untreated sex- and age-matched tgArcSwe mice (4 female and 6 male mice), (Figure 4). However, we found a trend indicating a lower plaque load in the cerebral cortex of drug treated females (p = 0.06) compared to vehicle-treated females. Comparisons of plaque load in cerebral cortex and thalamus in the same animal groups did not reveal any differences. Our conclusions are mostly based on the female group as the group of treated male mice was reduced due to an inadvertent loss of animals, although the results among the male mice pointed in the same direction.

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