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 g...
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| Format: | Article |
| Language: | English |
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BMC
2017-09-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13195-017-0305-3 |
| _version_ | 1818973816601182208 |
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| author | Anindit Chhibber Liqin Zhao |
| author_facet | Anindit Chhibber Liqin Zhao |
| author_sort | Anindit Chhibber |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T15:30:11Z |
| format | Article |
| id | doaj.art-313b2e076bc446a289e19ab293259ee9 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-20T15:30:11Z |
| publishDate | 2017-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-313b2e076bc446a289e19ab293259ee92022-12-21T19:35:38ZengBMCAlzheimer’s Research & Therapy1758-91932017-09-019111010.1186/s13195-017-0305-3ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brainAnindit Chhibber0Liqin Zhao1Department of Pharmacology and Toxicology, School of Pharmacy, University of KansasDepartment of Pharmacology and Toxicology, School of Pharmacy, University of KansasAbstract 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.http://link.springer.com/article/10.1186/s13195-017-0305-3Alzheimer’s disease (AD)DepressionApolipoprotein E (ApoE)Estrogen receptor β (ERβ)Brain-derived neurotrophic factor (BDNF)5-Hydroxytryptamine 2A (5-HT2A) |
| spellingShingle | Anindit Chhibber Liqin Zhao ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain Alzheimer’s Research & Therapy Alzheimer’s disease (AD) Depression Apolipoprotein E (ApoE) Estrogen receptor β (ERβ) Brain-derived neurotrophic factor (BDNF) 5-Hydroxytryptamine 2A (5-HT2A) |
| title | ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain |
| title_full | ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain |
| title_fullStr | ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain |
| title_full_unstemmed | ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain |
| title_short | ERβ and ApoE isoforms interact to regulate BDNF–5-HT2A signaling and synaptic function in the female brain |
| title_sort | erβ and apoe isoforms interact to regulate bdnf 5 ht2a signaling and synaptic function in the female brain |
| topic | Alzheimer’s disease (AD) Depression Apolipoprotein E (ApoE) Estrogen receptor β (ERβ) Brain-derived neurotrophic factor (BDNF) 5-Hydroxytryptamine 2A (5-HT2A) |
| url | http://link.springer.com/article/10.1186/s13195-017-0305-3 |
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