Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

Abstract

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 A␤1-42 and A␤1-40 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 (A␤PP) expression but did alter A␤PP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of A␤, decreased ␣A␤PP secretion, and increased A␤PP-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 A␤PP 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...

Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in female rats

“…Consistent with this possibility, a few studies have used direct bath application of E to hippocampal slices and reported an increase in long term potentiation, a cellular model for memory (Bi et al 2000;Foy et al 1999). However, it has been suggested that estrogen in vitro suppresses LH receptors so the in vitro effect of E could still be via suppression of LH signaling (Bowen et al, 2004). Estradiol treatment of ovxed females is also known to increase hippocampal spine density Leranth et al 2000Leranth et al , 2002Woolley et al 1990;Woolley and McEwen 1992), a change that is thought to underlie changes in memory ability, but it is unknown if any of the effects of E on spine density may actually be due to changes in LH.…”

“…Aβ oligomers are reported to disrupt long term potentiation (LTP) in vitro (Wang et al, 2002(Wang et al, , 2004 and in vivo (Walsh et al, 2002), and, appear to introduce memory impairment in AD mouse models (Cleary et al, 2004). In vitro research indicates that LH may increase Aβ by driving amyloid-β precursor protein (AβPP) processing to the amyoidogenic pathway (Bowen et al, 2004). However, whether LH/hCG affects AβPP processing via LH receptors or through an LH receptor-independent pathway is not known.…”

“…A series of studies have shown that levels of soluble Aβ correlate with the degree of cognitive impairment and disease progression in animal models and AD subjects (Kuo et al, 1996;McLean et al, 1999;Mucke et al, 2000;Naslund et al, 2000) whereas increasing evidence has suggested that soluble non-fibrillar Aβ rather than the insoluble fibrillar counterpart is important for the pathophysiology of the disease (Walsh 1999;Lambert et al, 2000). In addition, LH has been found to cause elevated levels of Aβ in neuroblastoma cells in vitro (Bowen et al, 2004), and the prolonged suppression of LH in both normal mice (Bowen et al, 2004) and an AD mouse model (Casadesus et al, 2006) has been shown to decrease Aβ load and aggregates, respectively, in vivo.…”

Advances in endocrinology of aging research, 2005–2006

“…In mice, the GnRH agonist leuprolide, which reduces gonadotropin and sex steroid levels, significantly reduced Aβ 1-42 and 1-40. Furthermore LH treatment of neuroblastoma cells in culture did not affect Aβ precursor protein (Aβpp) expression but did alter Aβpp processing toward the amyloidogenic pathway (Bowen et al 2004). A very recent paper (Casadesus et al 2006) showed that, in contrast to the adverse cognitive test results in estrogen plus progestin-treated postmenopausal women (Espeland et al 2004), suppression of LH by leuprolide significantly attenuated cognitive decline and decreased amyloid-β deposition in an aged transgenic mouse model of Alzheimer's disease compared with placebo-treated animals.…”

Human Chorionic Gonadotropin Increases β-Cleavage of Amyloid Precursor Protein in SH-SY5Y Cells

“…Studies in vitro using the M17 neuroblastoma cell line showed that treatment with LH increased Aβ production however the mechanism for this remains unclear (Bowen et al, 2004). Using a similar neuroblastoma cell model (SH-SY5Y), we sought to investigate specifically whether LH/hCG receptor activation triggers β-cleavage of APP.…”