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

作者：Chhibber Anindit; Zhao Liqin^*

来源：Alzheimer's Research and Therapy, 2017, 9(1): 79.

DOI：10.1186/s13195-017-0305-3

• Alzheimer's disease (AD)
• Depression
• Apolipoprotein E (ApoE)
• Estrogen receptor beta (ER beta)
• Brain-derived neurotrophic factor (BDNF)
• 5-Hydroxytryptamine 2A (5-HT2A)
• Synaptic function

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 epsilon 2, epsilon 3, and epsilon 4), and the epsilon 4 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 beta (ER beta) 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 ER beta-targeted (83-fold selectivity over ERa) 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 ER beta activity could provide a greater therapeutic benefit to non-ApoE4 carriers than to ApoE4 carriers in interventions for these brain disorders.

• 出版日期2017-9-21