title: 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.
authors.affiliation: Norwegian School of Veterinary Science, Oslo, Norway.
authors.forename: Syed
authors.initials: S
authors.lastname: Nuruddin
authors.affiliation: Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Gry Helen Enger
authors.initials: GH
authors.lastname: Syverstad
authors.affiliation: Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Sveinung
authors.initials: S
authors.lastname: Lillehaug
authors.affiliation: Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Trygve B
authors.initials: TB
authors.lastname: Leergaard
authors.affiliation: Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway; Department of Public Health & Caring Sciences / Geriatrics, Uppsala University, Uppsala, Sweden.
authors.forename: Lars N G
authors.initials: LN
authors.lastname: Nilsson
authors.affiliation: Norwegian School of Veterinary Science, Oslo, Norway.
authors.forename: Erik
authors.initials: E
authors.lastname: Ropstad
authors.affiliation: Norwegian School of Veterinary Science, Oslo, Norway.
authors.forename: Anette
authors.initials: A
authors.lastname: Krogenæs
authors.affiliation: Department of Neuropsychiatry and Psychosomatic Medicine, Division of Surgery and Clinical Neuroscience, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
authors.forename: Ira Ronit Hebold
authors.initials: IR
authors.lastname: Haraldsen
authors.affiliation: Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Reidun
authors.initials: R
authors.lastname: Torp
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004958:Estradiol / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000097:blood
chemical_list: D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol
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