Luteinizing hormone modulates cognition and amyloid-β 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

ABSTRACT 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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Available from: Craig S Atwood, Sep 29, 2015
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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.
    Journal of Alzheimer's disease: JAD 10/2014; 44(2). DOI:10.3233/JAD-141626 · 4.15 Impact Factor
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    • "In addition, the LH receptor knock-out mice show a significant decrease in the number of Ab plaques and protein content in the hippocampus and the cerebral cortex [34]. Several lines of evidence suggest that the raised serum LH levels could be a factor to induce Ab deposition [7] [50]. To understand how LH or FSH is involved in neurodegeneration and cognitive impairment in estrogen deficient animals, further studies are needed. "
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    ABSTRACT: This study aims to delineate the relationship among estrogen deficiency, neurodegeneration, and cognitive impairment of ovariectomized rats. Female Sprague-Dawley rats were ovariectomized and euthanized after 1-4month periods (M(0)-M(4) groups). Blood samples were collected for the determination of serum levels of 17β-estradiol (E(2)), luteinizing hormone (LH), and follicle stimulating hormone (FSH). Five consecutive days before the euthanization, cognitive performance of the rats was examined by Morris water maze test. After euthanization, the hippocampus was collected, and expression of the genes associated with amyloid plaques (App, Adam10 and Bace1) and neurofibrillary tangles (Tau4 and Tau3) were examined by real-time PCR. Serum E(2) levels were declined following 2weeks of ovariectomy. Conversely, serum FSH and LH levels were profoundly increased by 2weeks of ovariectomy for approximately 4 and 22 times, respectively. Cognitive impairments, indicated by the longer latency and distance, were observed only in the M(3) and M(4) groups. The Tau4 mRNA levels were significantly increased as early as 1month after ovariectomy (in the M(1) group; P<0.05), and tended to be increased further with the advancing time. Similarly, the Tau3 mRNA levels were increased by ovariectomy, but with the highest level in the M(1) group, and decreased thereafter. The mRNA levels of App, Adam10 and Bace1 were increased by ovariectomy, but significant differences were observed only in the M(4) group. These results indicate that estrogen deficiency can induce a sequence of events that results in the production of neurofibrillary tangles, amyloid deposition, and spatial memory deficit in rats.
    General and Comparative Endocrinology 10/2013; 181:316-323. DOI:10.1016/j.ygcen.2012.07.034 · 2.47 Impact Factor
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    • "GnRH regulates the release of luteinizing hormone, which is elevated in AD patients. The luteinizing hormone is known to be involved in the formation of beta amyloid (Aβ), which is a pathological hallmark of AD [46,47], and the neurotrophin signaling pathway regulates the signaling of neurons [48]. In AD and other neurodegenerative conditions, neurotrophin receptors (NTRs), such as p7NTR, bind to Aβ and nerve growth factors to promote cell death [49]. "
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    ABSTRACT: Background Identification of canonical pathways through enrichment of differentially expressed genes in a given pathway is a widely used method for interpreting gene lists generated from high-throughput experimental studies. However, most algorithms treat pathways as sets of genes, disregarding any inter- and intra-pathway connectivity information, and do not provide insights beyond identifying lists of pathways. Results We developed an algorithm (PathNet) that utilizes the connectivity information in canonical pathway descriptions to help identify study-relevant pathways and characterize non-obvious dependencies and connections among pathways using gene expression data. PathNet considers both the differential expression of genes and their pathway neighbors to strengthen the evidence that a pathway is implicated in the biological conditions characterizing the experiment. As an adjunct to this analysis, PathNet uses the connectivity of the differentially expressed genes among all pathways to score pathway contextual associations and statistically identify biological relations among pathways. In this study, we used PathNet to identify biologically relevant results in two Alzheimer’s disease microarray datasets, and compared its performance with existing methods. Importantly, PathNet identified de-regulation of the ubiquitin-mediated proteolysis pathway as an important component in Alzheimer’s disease progression, despite the absence of this pathway in the standard enrichment analyses. Conclusions PathNet is a novel method for identifying enrichment and association between canonical pathways in the context of gene expression data. It takes into account topological information present in pathways to reveal biological information. PathNet is available as an R workspace image from
    Source Code for Biology and Medicine 09/2012; 7(1). DOI:10.1186/1751-0473-7-10
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