ERβ and ApoE isoforms interact to regulate BDNF-5-HT(2A) signaling and synaptic function in the female brain.
ERβ and ApoE isoforms interact to regulate BDNF-5-HT(2A) signaling and synaptic function in the female brain.
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DOI：
10.1186/s13195-017-0305-3
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发表时间：
2017-09-21
期刊：
影响因子：
--
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Chhibber A;Zhao L
据报道，抑郁症通常在阿尔茨海默病（AD）患者中表现出来，并被认为是AD的危险因素。人载脂蛋白E（ApoE）基因存在三种主要亚型（编码为ε2、ε3和ε4），ε4等位基因与抑郁症和AD的发病率较高相关。虽然越来越多的证据表明这两种大脑疾病之间可能存在复杂的相互作用，ApoE可能在其中发挥作用，但其潜在机制在很大程度上尚不清楚。使用人ApoE 2、ApoE 3和ApoE 4基因靶向置换（hApoE-TR）小鼠模型，我们研究了ApoE亚型及其与雌激素受体β（ERβ）信号转导的潜在相互作用在调节抑郁症相关脑机制中的作用。我们在6个月大的雌性hApoE-TR小鼠中的初步分析表明，ApoE以亚型依赖性方式影响脑源性神经营养因子（BDNF）和5-羟色胺2A（5-HT 2A）5-羟色胺受体的表达，ApoE 4脑显示出最低水平的BDNF和最高水平的5-HT 2A。此外，突触前和突触后蛋白都下调，表明ApoE 4脑中存在突触缺陷。我们随后的分析显示，为期3个月的ERβ靶向（ERα的83倍选择性）植物雌激素饮食慢性治疗诱导ApoE 2和ApoE 3脑中的几种变化，包括5-HT 2A受体表达的显著降低和BDNF/原肌球蛋白受体激酶B和突触蛋白的增加。相比之下，ApoE 4大脑在很大程度上对治疗无反应，治疗组中仅选择突触蛋白增加。综上所述，这些结果表明，ApoE 4对女性大脑中的BDNF-5-HT 2A信号传导产生负面影响，这可能是ApoE 4介导的抑郁症风险增加的部分原因。在更大的范围内，这种机制可以作为抑郁症和与ApoE 4相关的AD之间的分子联系。在这些脑疾病的干预中，增强ERβ活性可以为非ApoE 4携带者提供比ApoE 4携带者更大的治疗益处。
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.
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影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
4
作者：
Butters, MA;Sweet, RA;DeKosky, ST
通讯作者：
DeKosky, ST
影响因子：
3.7
作者：
Chhibber A;Woody SK;Karim Rumi MA;Soares MJ;Zhao L
通讯作者：
Zhao L
影响因子：
--
作者：
Nautiyal KM;Hen R
通讯作者：
Hen R
影响因子：
--
作者：
Irie, Fumiko;Masaki, Kamal H.;White, Lon R.
通讯作者：
White, Lon R.