Estrogen Receptor β Regulates Brain Signaling Involved in Depression

Depression, a common, costly and recurrent disorder is associated with considerable morbidity and excess mortality. Several epidemiological and clinical studies have reported that women exhibit an increased risk for developing depression in comparison to men. This discrepancy has been attributed to the hormonal fluctuations occurring in the perimenopausal phase, however, the underlying molecular mechanism(s) are currently unknown. In addition, depression and depressive symptoms are common in individuals diagnosed with Late-onset Alzheimer disease (LOAD) and it is now well-established that a significant association exists between depression and LOAD. The human apolipoprotein E (APOE) gene exists as three major isoforms (ε2, ε3, and ε4) and the ε4 allele has been independently associated with a greater incidence for both depression and AD. Although mounting evidence has pointed to the potentially complex interaction between these two brain disorders in which APOE may play a role, the underlying mechanisms are largely unknown. Therefore, the purpose of this thesis was to a) characterize the mechanism(s) that underlie the etiology of depression in perimenopausal females and b) determine the impact of APOE status in the well reported interaction of depression and AD, with depression being an independent risk factor of AD. In the first chapter, we characterized the role of genomic estrogen signaling in the regulation of BDNF and 5HT2A receptor signaling. Our analyses in estrogen receptor (ER) knockout mouse models (ERα-/- and ERβ-/-) demonstrated that BDNF expression was significantly downregulated in ERβ-/- but not ERα-/- mice, and that the ERβ-/--mediated effect was brain-region specific. Further analyses in primary hippocampal neurons indicated that ERβ agonism significantly enhanced BDNF-TrkB signaling and the downstream signaling cascades involved in neurogenesis and synaptic plasticity. Our subsequent analysis in the hippocampus of ERβ-/- rats demonstrated that ERβ deficiency was associated with significantly elevated expression levels of 5HT2A receptor but not 5HT1A receptor. Moreover, our analyses in primary hippocampal neurons revealed that BDNF/TrkB signaling is likely an upstream regulator of the 5HT2A pathway. Collectively, these findings suggest that ERβ signaling dyshomeostasis during perimenopause results in the dysregulation of the BDNF-5HT2A network. These perturbations along with weakened synaptic plasticity may contribute to the overall female susceptibility for depression. Therefore, we hypothesize that timely intervention with an ERβ-targeted modulator could potentially attenuate this susceptibility and reduce the risk or ameliorate the clinical manifestation of depression. In the second chapter, we examined the impact of different APOE isoforms on neurotrophic and serotonergic signaling pathways in female brain. We hypothesized that APOE isoforms differentially regulate BDNF and 5HT2A signaling pathways with APOE4 resulting in overall dysregulation and APOE2 conferring neuroprotection. Our analyses in 6-month-old female humanized APOE mice (ApoE2, ApoE3, and ApoE4) demonstrated that BDNF and 5HT2A receptor expression levels were regulated in a genotype-depended manner with ApoE4 brain exhibiting the lowest level of BDNF and the highest level of 5HT2A. Additionally, several pre- and post-synaptic proteins were significantly downregulated in ApoE4 brain indicating a degree of synaptic deficit. Moreover, we find that chronic administration of an ERβ-targeted phytoestrogenic diet induced a number of changes in ApoE2 and ApoE3 brains, including a significant decrease in the expression of 5HT2A receptor and an increase in BDNF/TrkB and synaptic proteins whereas, in contrast, ApoE4 brain was largely unresponsive to the treatment. Collectively, these results indicate that APOE4 negatively impacts BDNF-5HT2A signaling in female brain, which could, in part, underlie the APOE4-mediated increased risk for depression. The data presented here supports our hypotheses that estrogen signaling significantly regulates BDNF 5HT2A signaling in female brain and thus can provide for a possible mechanistic explanation for depression in perimenopausal females. In addition the data also reveals significant modulation of BDNF 5HT2A signaling pathways and synaptic function in an ApoE genotype dependent manner, thus providing a possible underlying mechanism and therapeutic window for increased risk of AD in depressed patients

Estrogen receptor β in Alzheimer's disease: from mechanisms to therapeutics

Alzheimer's disease (AD) disproportionally affects women and men. The female susceptibility for AD has been largely associated with the loss of ovarian sex hormones during menopause. This review examines current understanding of the role of estrogen receptor β (ERβ) in the regulation of neurological health and its implication in the development and intervention of AD. Since its discovery in 1996, research conducted over the last 15-20 years has documented a great deal of evidence indicating that ERβ plays a pivotal role in a broad spectrum of brain activities from development to aging. ERβ genetic polymorphisms have been associated with cognitive impairment and increased risk for AD predominantly in women. The role of ERβ in the intervention of AD has been demonstrated by the alteration of AD pathology in response to treatment with ERβ-selective modulators in transgenic models that display pronounced plaque and tangle histopathological presentations as well as learning and memory deficits. Future studies that explore the potential interactions between ERβ signaling and the genetic isoforms of human apolipoprotein E (APOE) in brain aging and development of AD-risk phenotype are critically needed. The current trend of lost-in-translation in AD drug development that has primarily been based on early-onset familial AD (FAD) models underscores the urgent need for novel models that recapitulate the etiology of late-onset sporadic AD (SAD), the most common form of AD representing more than 95% of the current human AD population. Combining the use of FAD-related models that generally have excellent face validity with SAD-related models that hold more reliable construct validity would together increase the predictive validity of preclinical findings for successful translation into humans

ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain

Abstract Background Depression has been reported to be commonly manifested in patients with Alzheimer’s disease (AD) and is considered a risk factor for AD. The human apolipoprotein E (ApoE) gene exists in three major isoforms (coded by ε2, ε3, and ε4), and the ε4 allele has been associated with a greater incidence of both depression and AD. Although mounting evidence points to the potentially complex interaction between these two brain disorders in which ApoE might play a role, the underlying mechanisms are largely unknown. Methods Using human ApoE2, ApoE3, and ApoE4 gene-targeted replacement (hApoE-TR) mouse models, we investigated the role of ApoE isoforms and their potential interactions with estrogen receptor β (ERβ) signaling in modulating the brain mechanisms involved in depression. Results Our initial analyses in 6-month-old female hApoE-TR mice demonstrated that ApoE influenced the expression of brain-derived neurotrophic factor (BDNF) and the 5-hydroxytryptamine 2A (5-HT2A) serotonin receptor in an isoform-dependent manner, with the ApoE4 brain exhibiting the lowest level of BDNF and the highest level of 5-HT2A. In addition, both presynaptic and postsynaptic proteins were downregulated, indicating a synaptic deficit in ApoE4 brains. Our subsequent analyses revealed that a 3-month chronic treatment with an ERβ-targeted (83-fold selectivity over ERα) phytoestrogenic diet induced several changes in ApoE2 and ApoE3 brains, including a significant decrease in the expression of 5-HT2A receptors and an increase in BDNF/tropomyosin receptor kinase B and synaptic proteins. In contrast, ApoE4 brains were largely unresponsive to the treatment, with an increase only in select synaptic proteins in the treated group. Conclusions Taken together, these results indicate that ApoE4 negatively impacts BDNF–5-HT2A signaling in the female brain, which could in part underlie the ApoE4-mediated increased risk for depression. In a larger context, this mechanism could serve as a molecular link between depression and AD associated with ApoE4. Enhancing ERβ activity could provide a greater therapeutic benefit to non-ApoE4 carriers than to ApoE4 carriers in interventions for these brain disorders