Luteinizing hormone modulates cognition and amyloid-deposition in Alzheimer APP transgenic mice

Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 05/2006; 1762(4):447-52. DOI: 10.1016/j.bbadis.2006.01.008
Source: PubMed


Until recently, the study of hormonal influences in Alzheimer disease was limited to the role of sex steroids. Despite numerous epidemiological studies supporting a protective role for estrogen in Alzheimer disease, recent studies show that estrogen administration in elderly women increases the risk of disease. Reconciling these contradictory reports, we previously hypothesized that other hormones of the hypothalamic-pituitary-gonadal axis, such as luteinizing hormone, may be involved in the onset and development of the disease. In this regard, luteinizing hormone is elevated in Alzheimer disease and is known to modulate amyloidogenic processing of amyloid-beta protein precursor. Therefore, in this study, to evaluate the therapeutic potential of luteinizing hormone ablation, we administered a gonadotropin-releasing hormone analogue, leuprolide acetate, to an aged transgenic mouse model of Alzheimer disease (Tg 2576) and measured cognitive Y-maze performance and amyloid-beta deposition after 3 months of treatment. Our data indicate that luteinizing hormone ablation significantly attenuated cognitive decline and decreased amyloid-beta deposition as compared to placebo-treated animals. Importantly, leuprolide acetate-mediated reduction of amyloid-beta correlated with improved cognition. Since both cognitive loss and amyloid-beta deposition are features of Alzheimer disease, leuprolide acetate treatment may prove to be a useful therapeutic strategy for this disease.

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    • "An entry was scored when the four paws of the animals were completely in the arm of the Y-maze. The percentage alternation, which gives a measure of working memory, was calculated by dividing the total number of alternations by the total number of arm entries, minus two and multiplied by 100 [21]. An alternation behavior was defined as consecutive entries into all three arms (i.e. "

    Full-text · Article · Jan 2015 · Journal of Behavioral and Brain Science
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    • "Suppression of gonadotropins with Lupron improves cognitive performance in aged A␤PPtransgenic mice [2] while increases in luteinizing hormone (LH)/human chorionic gonadotropin (hCG) have been attributed to cognitive decline in ovariectomized rats [11], LH␤-transgenic mice [12], and ovariectomized C57/Bl6 mice [13]. Moreover, Lupron treatment has been shown to decrease amyloid-␤ (A␤) production in C57/Bl6 mice [8] and A␤ load in aged A␤PP-transgenic mice [2]. The role of LH in mediating A␤PP processing was confirmed in a bigenic mouse model that expresses A␤PPsw + in the background of a LH receptor (Lhr) knockout (A␤PPsw + /Lhr −/− ; [14]). "
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    ABSTRACT: To test the efficacy and safety of leuprolide acetate (Lupron Depot®) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot® (11.25 mg leuprolide acetate), high dose Lupron Depot® (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: -0.54, -8.00, and -6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD.
    Full-text · Article · Oct 2014 · Journal of Alzheimer's disease: JAD
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    • "Treatment groups were chosen randomly and received physiological saline (OVX+SAL; n = 6) (0.9%), leuprolide acetate (OVX+LA; n = 6) (3.6 lg/day) or 17b-estradiol (OVX+E 2 ; n = 5) (1.1 ng/day) in Alzet pumps (Pump 1004, Durect Corporation, Cupertino, CA, USA) implanted once a month for 3 months. It has been previously shown that a slow-release formulation of LA significantly reduces LH levels and improves cognitive function in Tg2576 mice (Casadesus et al. 2006) as well as female wild-type mice (Bryan et al. 2010), and the estrogen dosage was selected from previous literature that showed cognitive improvement in OVX rats (Takuma et al. 2007). All animals were weighed prior to initial capsule implant and before each capsule replacement for the 3-month- treatment duration as an analysis of health. "
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    ABSTRACT: Development of Alzheimer's disease (AD) has been linked to the deregulation of estrogen and gonadotropins such as luteinizing hormone (LH). In this study, we found increases in AD pathology in the hippocampi of aged female 3xTg AD mice after ovariectomy that were unable to be reduced by estrogen therapy or downregulation of serum LH levels. Despite the lack of effect of these treatments on AD pathology, downregulation of serum LH but not estrogen improved factors associated with neuronal plasticity such as spatial memory, inhibition of GSK3β, expression of beta-catenin, and BDNF transcription. Contrasting previous studies in younger mice, estrogen replacement was not able to rescue behavioral deficits, reduced GSK3β inhibition and increased hippocampal phosphorylation of tau. Of critical importance, serum LH was negatively correlated with brain LH in regions associated with spatial memory, and increases in brain LH correlated with cognitive improvement. This paralleled changes in human female AD brains which showed a significant reduction in brain LH mRNA compared to healthy age- and PMI-matched controls. Taken together, these findings should promote further research into the LH-dependent mechanisms associated with AD cognitive deficits as well as the effects of estrogen within the aged brain. This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2014 · Journal of Neurochemistry
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