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      Direct Exposure of Guinea Pig CNS to Human Luteinizing Hormone Increases Cerebrospinal Fluid and Cerebral Beta Amyloid Levels

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          Background/Aims: Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key protein in Alzheimer’s disease (AD) pathogenesis. While LH and components required for LH receptor signalling are present in the brain, their role in the CNS remains unclear. In vitro, LH has been shown to facilitate neurosteroid production and alter Aβ metabolism. However, whether LH can directly modulate cerebral Aβ levels in vivo has not previously been studied. In this study, we investigated the effect of chronic administration of LH to the guinea pig CNS on cerebral Aβ levels. Methods: Gonadectomised male animals were administered, via cortical placement, either placebo or LH slow-release pellets. At 14 and 28 days after treatment, animals were sacrificed. Brain, plasma and CSF were collected and Aβ levels measured via ELISA. Levels of the Aβ precursor protein (APP) and the neurosteroidogenic enzyme cytochrome P450 side-chain cleavage enzyme (P450scc) were also assayed. Results: An increase in CSF Aβ40 levels was observed 28 days following treatment. These CSF data also reflected changes in Aβ40 levels observed in brain homogenates. No change was observed in plasma Aβ40 levels but APP and its C-terminal fragments (APP-CTF) were significantly increased in response to LH exposure. Protein expression of P450scc was increased after 28 days of LH exposure, suggesting activation of the LH receptor. Conclusion: These data indicate that direct exposure of guinea pig CNS to LH results in altered brain Aβ levels, perhaps due to altered APP expression/metabolism.

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          Most cited references 27

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          Clearance mechanisms of Alzheimer's amyloid-beta peptide: implications for therapeutic design and diagnostic tests.

          Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-beta (Abeta) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Abeta is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Abeta leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Abeta are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Abeta clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Abeta ELISAs are discussed, as are the more promising results of Abeta imaging by positron emission tomography. Current knowledge of Abeta-binding proteins and Abeta-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Abeta remains an attractive therapeutic strategy, and improved understanding of Abeta clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.
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            Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition.

            Hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause have been implicated in the pathogenesis of Alzheimer's disease (AD). Experimental support for this has come from studies demonstrating an increase in amyloid-beta (Abeta) deposition following ovariectomy/castration. Because sex steroids and gonadotropins are both part of the HPG feedback loop, any loss in sex steroids results in a proportionate increase in gonadotropins. To assess whether Abeta generation was due to the loss of serum 17beta-estradiol or to the up-regulation of serum gonadotropins, we treated C57Bl/6J mice with the anti-gonadotropin leuprolide acetate, which suppresses both sex steroids and gonadotropins. Leuprolide acetate treatment resulted in a 3.5-fold (p < 0.0001) and a 1.5-fold (p < 0.024) reduction in total brain Abeta1-42 and Abeta1-40 concentrations, respectively, after 8 weeks of treatment. To further explore the role of gonadotropins in promoting amyloidogenesis, M17 neuroblastoma cells were treated with the gonadotropin luteinizing hormone (LH) at concentrations equivalent to early adulthood (10 mIU/ml) or post-menopause/andropause (30 mIU/ml). LH did not alter amyloid-beta precursor protein (AbetaPP) expression but did alter AbetaPP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of Abeta, decreased alphaAbetaPP secretion, and increased AbetaPP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote Abeta secretion and deposition in the aging brain. Suppression of the age-related increase in serum gonadotropins using anti-gonadotropin agents may represent a novel therapeutic strategy for AD.
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              Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways.

              Normal, age-related depletion of the androgen testosterone is a risk factor for Alzheimer's disease (AD) in men. Previously, we reported that experimental androgen depletion significantly accelerates development of AD-like neuropathology in the 3xTg-AD triple-transgenic mouse model of AD, an effect prevented by androgen treatment. Because testosterone is metabolized in brain into both the androgen dihydrotestosterone (DHT) and the estrogen 17β-estradiol (E2), testosterone can mediate its effects through androgen and or estrogen pathways. To define the role of androgen and estrogen pathways in regulation of AD-like neuropathology, we compared the effects of testosterone (T) and its metabolites DHT and E2 in male 3xTg-AD mice depleted of endogenous sex steroid hormones by gonadectomy (GDX). Male 3xTg-AD mice were sham GDX or GDX, immediately treated with vehicle, T, DHT, or E2, and 4 months later evaluated for two indices of AD-like neuropathology, β-amyloid (Aβ) accumulation and tau hyperphosphorylation. In comparison to sham GDX mice, we observed a significant increase in Aβ accumulation in GDX mice in subiculum, hippocampus, and amygdala. Treatment of GDX mice with T prevented the increased Aβ accumulation in all three brain regions. DHT treatment yielded similar results, significantly reducing Aβ accumulation across brain regions. Interestingly, E2 prevented Aβ accumulation in hippocampus but exerted only partial effects in subiculum and amygdala. Levels of tau hyperphosphorylation in sham GDX male 3xTg-AD mice were modest and only slightly increased by GDX. Treatment of GDX mice with T or E2 but not DHT reduced tau hyperphosphorylation to levels lower than observed in sham animals. These data suggest that testosterone regulates Aβ pathology through androgen and estrogen pathways and reduces tau pathology largely through estrogen pathways. These findings further define hormone pathways involved in regulation of AD-related pathology, information that is important for understanding disease etiology and developing pathway-specific hormone interventions. Copyright © 2010 Elsevier B.V. All rights reserved.

                Author and article information

                S. Karger AG
                December 2011
                05 October 2011
                : 94
                : 4
                : 313-322
                aCentre of Excellence for Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, W.A., and bSir James McCusker Alzheimer’s Disease Research Unit, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Hollywood Private Hospital, Nedlands, W.A., Australia; cMedical Faculty, Pelita Harapan University-Neuroscience Centre, Siloam Hospital, Tangerang, Indonesia; dNathan Kline Institute, Orangeburg, N.Y., USA
                Author notes
                *Prof. Ralph N. Martins, Edith Cowan University, 270 Joondalup Drive (Building 17), Joondalup, WA 6027 (Australia), Tel. +61 8 6304 5456, E-Mail r.martins@ecu.edu.au
                330812 Neuroendocrinology 2011;94:313–322
                © 2011 S. Karger AG, Basel

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                Page count
                Figures: 6, Pages: 10
                Original Paper


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