Date Published: September 21, 2017
Publisher: BioMed Central
Author(s): Anindit Chhibber, Liqin Zhao.
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.
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.
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.
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.
Depression manifests in up to 50% of patients with Alzheimer’s disease (AD) [1–3] and is associated with increased neurological impairment  and mortality . In addition, depression is an independent risk factor for the development of mild cognitive impairment (MCI) and for the progression from MCI to AD , contributing to at least a twofold increased AD risk compared with control subjects without depression [7–10]. Furthermore, the severity of the depressive phenotype (measured by the number of depressive symptoms in patients with depression) has been shown to be directly associated with an increased risk of developing AD, with each depressive symptom increasing the risk of AD development by approximately 20% compared with control subjects without depression . Although a number of clinical studies have indicated the interaction between depression and AD, the underlying pathophysiological mechanisms are not understood.
Recent clinical studies have identified a significant association between depression and ApoE4, a major genetic risk factor for the development of AD . Although the association has been well documented, the underlying molecular mechanisms leading to this probable association are unknown. On the basis of the literature and our own work, we hypothesize that the three ApoE isoforms differentially modulate neurotrophic and serotonergic pathways implicated in the pathophysiology of depression. The ApoE4 isoform causes significant dysregulation, thus increasing an individual’s risk of developing depression, and the ApoE2 isoform provides neuroprotection against the disease. To examine this hypothesis, we used 6-month-old human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mouse models and found that BDNF and 5-HT2A receptor expression was significantly impacted in an ApoE isoform-dependent manner. Specifically, BDNF significantly decreased, whereas 5-HT2A receptor significantly increased, in ApoE4 animals compared with both ApoE2 and ApoE3 animals (Fig. 1). These data correspond with clinical findings of increased 5-HT2A mRNA and protein expression levels [39–41] and decreased BDNF expression levels in patients with depression [42, 43]. Thus, the findings imply that the ApoE4-mediated increased risk of developing depression could be partially attributed to the upregulation of 5-HT2A and downregulation of BDNF signaling in ApoE4 carriers compared with carriers of the other two isoforms.
Our findings illustrate a possible mechanism involving BDNF–5-HT2A signaling pathways by which ApoE isoforms confer differential risk for depression (Fig. 6). In a larger context, this mechanism could serve as a link between depression and AD associated with ApoE4. In addition, our findings suggest that enhancing ERβ activity could provide a greater therapeutic benefit for ApoE2 and ApoE3 carriers than for ApoE4 carriers in interventions for depression. These preliminary data warrant further in-depth investigations of the pharmacological and behavioral relevance of the molecular differences identified in this study in depression models.Fig. 6Estrogen receptor β (ERβ) interacts with apolipoprotein E (ApoE) in the regulation of brain-derived neurotrophic factor (BDNF)–5-hydroxytryptamine 2A (5-HT2A) signaling and synaptic function in the female brain. The findings presented indicate that ApoE isoforms differentially modulate the BDNF–5-HT2A signaling and synaptic function in the female brain. Specifically, compared with ApoE2 and ApoE3, the presence of the ApoE4 allele exerts a largely negative impact on these signaling pathways, which predisposes the brain to an increased risk for depression, which further increases the risk for Alzheimer’s disease (AD). ERβ signaling positively modulates these brain pathways primarily in ApoE2 and ApoE3 brains, whereas it has a minimal role in the ApoE4 brain, implicating the potential interaction of ERβ signaling and ApoE isoforms in the modulation of certain functions in the female brain