Elevated mRNA-Levels of Gonadotropin-Releasing Hormone and Its Receptor in Plaque-Bearing Alzheimer's Disease Transgenic Mice

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.

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

“…The HPG axis is regulated precisely by GnRH which plays a central role in both the reproductive functions and general hormonal control. Although the concentration of circulating GnRH is very low due to its short half-life, it is a prime factor in the pathogenesis of AD [43]. It is reported that GnRH induces adult neurogenesis in several brain regions typically afflicted by AD neuropathology [40].…”

Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease

“…Interestingly, at least one other AD mouse model presumably has elevated levels of GnRH and LH. Recently, it was found that tgArcSwe mice, which carry two prominent AβPP mutations, have elevated mRNA levels of both GnRH and GnRH receptors (Nuruddin et al, 2014). Although LH was not measured, it is likely that it was increased because GnRH was increased.…”

Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions

“…40 More recently, it has been reported a higher hippocampal level of GnRH and GnRHR mRNA in both male and female plaque-bearing AD transgenic mice (tgArcSwe), respect to age matched controls. 41 The treatment of these animals with the GnRHa leuprolide caused sex-related significant down-regulation of the expression of both the peptide and of its receptor, even though without significant changes in the plaque load; this may be suggestive of an insufficient effect of GnRHR activation in a more severe and advanced stage of the disease or an effect of GnRHa weaker than the transgene phenotype of the animal model. 41 Finally, clinical trials using leuprolide acetate has been shown to stabilize cognition in women with mild-to-moderate AD.…”

“…41 The treatment of these animals with the GnRHa leuprolide caused sex-related significant down-regulation of the expression of both the peptide and of its receptor, even though without significant changes in the plaque load; this may be suggestive of an insufficient effect of GnRHR activation in a more severe and advanced stage of the disease or an effect of GnRHa weaker than the transgene phenotype of the animal model. 41 Finally, clinical trials using leuprolide acetate has been shown to stabilize cognition in women with mild-to-moderate AD. 42 These findings clearly support the role of GnRH as a potential regulator of AD pathogenesis and lead to view the hypothalamic GnRH-NF-kB axis as an interesting mediator of aging-related neurodegenerative processes.…”

“…41 Finally, clinical trials using leuprolide acetate has been shown to stabilize cognition in women with mild-to-moderate AD.…”