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- (A) 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 A generation was due to the loss of serum 17-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 A1-42 and A1-40 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- precursor protein (APP) expression but did alter APP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of A, decreased ␣APP secretion, and increased APP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote A 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.Alzheimer's disease (AD) 1 is a neurodegenerative disorder of the elderly that leads to progressive memory loss, impairments in behavior, language, visuo-spatial skills, and ultimately death. The one or more underlying biochemical mechanisms leading to AD are unknown. Genetic studies have shown that mutations in APP and the presenilin genes lead to early onset (Յ65 years) AD, which accounts for ϳ5% of all AD cases. The vast majority of these mutations promote the overproduction and deposition of amyloid- (A) (1-7), the major component of the extracellular amyloid plaques, in the hippocampus and frontal cortex (8,9). Amyloid deposition also is a hallmark of the late-onset or "sporadic" form of AD, which accounts for ϳ95% of AD cases. The primary factors responsible for A deposition and disease progression in late onset AD remain to be elucidated.Aging, the strongest risk factor for late-onset AD, is associated with major changes in serum concentrations of all hormones that comprise the hypothalamic-pituitary-gonadal (HPG) axis, including declines in the serum concentrations of the sex steroids, 17-estradiol and testosterone. Such changes have been correlated with the prevalence of the disease (e.g. Refs. 10 -14), and it has been shown that there is a decreased i...
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.
In individuals with Alzheimer's disease (AD), there is a two‐fold elevation in the serum concentrations of the gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone compared to age‐matched controls. Whether this plays a role in disease pathogenesis is unclear. Nonetheless, gonadotropins are known to cross the blood brain barrier and the highest density of gonadotropin receptors in the brain are found within the hippocampus. We report for the first time the localization of LH in the cytoplasm of pyramidal neurons. In addition, we find a significant increase in LH in the cytoplasm of pyramidal neurons and neurofibrillary tangles of AD brain compared to age‐matched control brain. Whereas the functional consequences of increased neuronal LH are unknown, it is notable that LH is primarily localized to those neurons that are known to be vulnerable to Alzheimer's disease‐related neurodegeneration. Elevated serum and cortical neuron levels of LH, coupled with the decline in sex steroid production, could play important roles in the pathogenesis of AD. © 2002 Wiley‐Liss, Inc.
Leuprolide acetate is a synthetic nonapeptide that is a potent gonadotropin-releasing hormone receptor (GnRHR) agonist used for diverse clinical applications, including the treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty and in vitro fertilization techniques. As its basic mechanism of action, leuprolide acetate suppresses gonadotrope secretion of luteinizing hormone and follicle-stimulating hormone that subsequently suppresses gonadal sex steroid production. In addition, leuprolide acetate is presently being tested for the treatment of Alzheimer's disease, polycystic ovary syndrome, functional bowel disease, short stature, premenstrual syndrome and even as an alternative for contraception. Mounting evidence suggests that GnRH agonist suppression of serum gonadotropins may also be important in many of the clinical applications described above. Moreover, the presence of GnRHR in a multitude of non-reproductive tissues including the recent discovery of GnRHR expression in the hippocampi and cortex of the human brain indicates that GnRH analogs such as leuprolide acetate may also act directly via tissue GnRHRs to modulate (brain) function. Thus, the molecular mechanisms underlying the therapeutic effect of GnRH analogs in the treatment of these diseases may be more complex than originally thought. These observations also suggest that the potential uses of GnRH analogs in the modulation of GnRH signaling and treatment of disease has yet to be fully realized.
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