Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall Room 2046, Lawrence, KS, 66045, USA.
Neuroscience Graduate Program, University of Kansas, Lawrence, KS, USA.
Alzheimers Res Ther. 2017 Sep 21;9(1):79. doi: 10.1186/s13195-017-0305-3.
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-HT) serotonin receptor in an isoform-dependent manner, with the ApoE4 brain exhibiting the lowest level of BDNF and the highest level of 5-HT. 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-HT 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-HT 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.
抑郁症已被报道在阿尔茨海默病（AD）患者中普遍存在，被认为是 AD 的一个风险因素。人类载脂蛋白 E（ApoE）基因存在三种主要的异构体（由 ε2、ε3 和 ε4 编码），ε4 等位基因与抑郁症和 AD 的发生率增加有关。尽管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，但潜在机制在很大程度上仍是未知的。
使用人类 ApoE2、ApoE3 和 ApoE4 基因靶向替换（hApoE-TR）小鼠模型，我们研究了 ApoE 异构体的作用及其与雌激素受体 β（ERβ）信号的潜在相互作用，以调节与抑郁相关的大脑机制。
我们在 6 个月大的雌性 hApoE-TR 小鼠中的初步分析表明，ApoE 以依赖于异构体的方式影响脑源性神经营养因子（BDNF）和 5-羟色胺 2A（5-HT）血清素受体的表达，其中 ApoE4 大脑表现出最低水平的 BDNF 和最高水平的 5-HT。此外，突触前和突触后蛋白都下调，表明 ApoE4 大脑存在突触缺陷。我们随后的分析表明，3 个月的 ERβ 靶向（对 ERα 的选择性为 83 倍）植物雌激素饮食治疗导致 ApoE2 和 ApoE3 大脑发生了几种变化，包括 5-HT 受体表达显著下降，BDNF/原肌球蛋白受体激酶 B 和突触蛋白增加。相比之下，ApoE4 大脑对治疗反应不大，仅在治疗组中选择性增加了一些突触蛋白。
总的来说，这些结果表明，ApoE4 对女性大脑中的 BDNF-5-HT 信号产生负面影响，这可能在一定程度上解释了 ApoE4 介导的抑郁症风险增加。从更大的角度来看，这种机制可以作为与 ApoE4 相关的抑郁症和 AD 之间的分子联系。增强 ERβ 活性可能会为这些大脑疾病的干预措施中的非 ApoE4 携带者提供比 ApoE4 携带者更大的治疗益处。
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