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

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.