No 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.

J. Neurochem. (2010) 112, 870–881. Abstract Declining levels of estrogen in women result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by hormone replacement therapy. However, the role of post‐menopausal gonadotropin increases on cognition has not been evaluated. Here, we demonstrate that the down‐regulation of ovariectomy‐driven LH elevations using the gonadotropin releasing hormone super‐analogue, leuprolide acetate, improves cognitive function in the Morris water maze and Y‐maze tests in the absence of E2. Furthermore, our data suggest that these effects are independent of the modulation of estrogen receptors α and β, or activation of CYP19 and StAR, associated with the production of endogenous E2. Importantly, pathways associated with improved cognition such as CaMKII and GluR1‐Ser831 are up‐regulated by leuprolide treatment but not by chronic long‐term E2 replacement suggesting independent cognition‐modulating properties. Our findings suggest that down‐regulation of gonadotropins is as effective as E2 in modulating cognition but likely acts through different molecular mechanisms. These findings provide a potential novel protective strategy to treat menopause/age‐related cognitive decline and/or prevent the development of AD.

Age-related changes in reproductive hormone levels are a well-known risk factor for the development of cognitive dysfunction and dementia in women. We and others have shown an important contribution of gonadotropins in this process. Lowering serum gonadotropin levels is able to rescue cognitive function in Alzheimer’s disease and menopause models, but whether this is time-dependent and the exact mechanism through which gonadotropins regulate cognitive function is unknown. We show that pharmacologically lowering serum levels of luteinizing hormone lead to cognitive improvement immediately after ovariectomy and with a 4 month interval after ovariectomy, when the benefits of 17β-estradiol are known to disappear in rodents. Importantly, we show that these improvements are associated with spine density changes at both time points. These findings suggest a role of luteinizing hormone in learning and memory and neuroplasticity processes as well as provide an alternative therapeutic strategy of menopause associated cognitive loss.

No abstract