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Alzheimers Res Ther. 2017 Sep 21;9(1):79. doi: 10.1186/s13195-017-0305-3.

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

Author information

1
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall Room 2046, Lawrence, KS, 66045, USA.
2
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall Room 2046, Lawrence, KS, 66045, USA. lzhao@ku.edu.
3
Neuroscience Graduate Program, University of Kansas, Lawrence, KS, USA. lzhao@ku.edu.

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.

KEYWORDS:

5-Hydroxytryptamine 2A (5-HT2A); Alzheimer’s disease (AD); Apolipoprotein E (ApoE); Brain-derived neurotrophic factor (BDNF); Depression; Estrogen receptor β (ERβ); Synaptic function

PMID:
28934977
PMCID:
PMC5607839
DOI:
10.1186/s13195-017-0305-3
[Indexed for MEDLINE]
Free PMC Article

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