Down‐regulation of serum gonadotropins but not estrogen replacement improves cognition in aged‐ovariectomized 3xTg AD female mice

Abstract

Development of Alzheimer’s disease (AD) has been linked to the de-regulation 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 down-regulation of serum LH levels. Despite the lack of effect of these treatments on AD pathology, down-regulation of serum LH but not estrogen improved factors associated with neuronal plasticity such as spatial memory, inhibition of glycogen synthase kinase-3 beta, expression of beta-catenin, and brain-derived neurotrophic factor transcription. Contrasting previous studies in younger mice, estrogen replacement was not able to rescue behavioral deficits, reduced glycogen synthase kinase-3 beta 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.

Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease

“…In this study, treatment with leuprolide acetate resulted in a behavioral rescue (Casadesus et al, 2006). In a second transgenic mouse model of AD (3xTg AD), administration of leuprolide acetate was not only able to rescue cognitive deficits induced by ovx, but was also significantly more effective than estradiol administration at rescuing these deficits (Palm et al, 2014). A similar phenomenon was observed with the use of estrogen versus Antide in ovx female rats (Ziegler and Thornton, 2010).…”

“…Surprisingly, however, addition of estrogen, but not leuprolide acetate, actually resulted in an increased plaque load in the hippocampus of this transgenic model when compared to ovx animals given saline treatment. Leuprolide acetate treatment, but not estrogen, improved transcription of a number of genes (Palm et al, 2014), including beta-catenin, which has been associated with memory improvement (Maguschak and Ressler, 2008;Toledo and Inestrosa, 2010), and BDNF (Palm et al, 2014). Interestingly, peripheral administration of leuprolide acetate may have neural effects which might work in contest with its actions within the HPG axis, at least in this transgenic strain.…”

“…Interestingly, peripheral administration of leuprolide acetate may have neural effects which might work in contest with its actions within the HPG axis, at least in this transgenic strain. Treatment of ovx 3xTg-AD females with leuprolide acetate resulted in an increase in LH in the superior colliculi, an effect not observed with estrogen treatment (Palm et al, 2014). This upregulation of neural LH may occur independently of the leuprolide acetate's serum downregulation of pituitary-derived LH, and may act as a confounding factor, contributing to the failure of leuprolide acetate treatment to work as expected.…”

“…These include abnormally hyper-phosphorylated neurofibrillary tau tangles, amyloid beta (Aβ) plaque deposits, and neuronal cell death (Niikura et al, 2002;Obulesu and Lakshmi, 2014). There is also decreased neurogenesis and plasticity in hippocampal and cortical regions (Gandy and Dekosky, 2013;Iqbal and Grundke-Iqbal, 2011;Revett et al, 2013) concomitant with decreased levels of the neurotrophic factor BDNF, a key modulator of synaptic plasticity (Palm et al, 2014;Phillips et al, 1991).…”

“…In a number of experiments, Antide or leuprolide was administered to block pituitary LH, and it was assumed that the resulting behavioral and histopathological results were due to the downregulation of LH rather than GnRH or FSH (Bowen et al, 2004;Bryan et al, 2010;Palm et al, 2014;Ziegler and Thornton, 2010). However, GnRH and FSH receptors have been found in the hippocampus (Jennes and Conn, 1994;Chu et al, 2008;Schang et al, 2011;Wilson et al, 2007).…”