Supakul Sopak, Oyama Chisato, Hatakeyama Yuki, Maeda Sumihiro, Okano Hideyuki
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
Department of Electrical Engineering and Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Regen Ther. 2024 Jan 12;25:250-263. doi: 10.1016/j.reth.2023.12.018. eCollection 2024 Mar.
17β-Estradiol (E2) is a sex hormone that has been previously demonstrated to have neurotherapeutic effects on animal models of Alzheimer's disease (AD). However, clinical trials on E2 replacement therapy for preventing AD onset yielded inconsistent results. Therefore, it is imperative to clarify the therapeutic effects of E2 on human cells. In this study, we utilized induced pluripotent stem cells (iPSCs) derived from multiple AD donors to explore the therapeutic effects of E2 on the model of human cells.
We conducted a systematic review and meta-analysis using a random-effects model of the previously reported AD clinical trials to summarize the effects of E2 replacement therapy on AD prevention. Subsequently, we induced iPSCs from the donors of the healthy control (1210B2 line (female) and 201B7 line (female)), the familial AD (APP V717L line (female) and APP KM670/671NL line (female)), and the sporadic AD (UCSD-SAD3.7 line (APOE ε3/ε3) (male), UCSD-SAD7D line (APOE ε3/ε4) (male), and TMGH-1 line (APOE ε3/ε3) (female)), then differentiated to neurons. In addition to the mono-culture model of the neurons, we also examined the effects of E2 on the co-culture model of neurons and astrocytes.
The meta-analysis of the clinical trials concluded that E2 replacement therapy reduced the risk of AD onset (OR, 0.69; 95 % confidence interval [CI], 0.53-0.91; I = 82 %). Neural models from the iPSCs of AD donors showed an increase in secreted amyloid-beta (Aβ) levels in the mono-culture model and an astrogliosis-like phenotype in the co-culture model. E2 treatment to the neuronal models derived from the iPSCs enhanced neuronal activity and increased neurite complexity. Furthermore, E2 treatment of the co-culture model ameliorated the astrogliosis-like phenotype. However, in contrast to the previous reports using mouse models, E2 treatment did not change AD pathogenesis, including Aβ secretion and phosphorylated tau (pTau) accumulation.
E2 treatment of the human cellular model did not impact Aβ secretion and pTau accumulation, but promoted neuronal plasticity and alleviated the astrogliosis-like phenotype. The limited effects of E2 may give a clue for the mixed results of E2 clinical trials.
17β-雌二醇（E2）是一种性激素，先前已证明其对阿尔茨海默病（AD）动物模型具有神经治疗作用。然而，关于E2替代疗法预防AD发病的临床试验结果并不一致。因此，必须阐明E2对人类细胞的治疗作用。在本研究中，我们利用来自多个AD供体的诱导多能干细胞（iPSC）来探索E2对人类细胞模型的治疗作用。
我们使用随机效应模型对先前报道的AD临床试验进行了系统评价和荟萃分析，以总结E2替代疗法对AD预防的效果。随后，我们从健康对照供体（1210B2系（女性）和201B7系（女性））、家族性AD供体（APP V717L系（女性）和APP KM670/671NL系（女性））以及散发性AD供体（UCSD-SAD3.7系（APOE ε3/ε3）（男性）、UCSD-SAD7D系（APOE ε3/ε4）（男性）和TMGH-1系（APOE ε3/ε3）（女性））诱导iPSC，然后将其分化为神经元。除了神经元的单培养模型外，我们还研究了E2对神经元与星形胶质细胞共培养模型的影响。
对临床试验的荟萃分析得出结论，E2替代疗法降低了AD发病风险（比值比，0.69；95%置信区间[CI]，0.53 - 0.91；I² = 82%）。来自AD供体iPSC的神经模型在单培养模型中显示分泌的淀粉样β蛋白（Aβ）水平升高，在共培养模型中显示出星形胶质细胞增生样表型。对源自iPSC的神经元模型进行E2处理可增强神经元活性并增加神经突复杂性。此外，对共培养模型进行E2处理可改善星形胶质细胞增生样表型。然而，与先前使用小鼠模型的报道不同，E2处理并未改变AD发病机制，包括Aβ分泌和磷酸化tau（pTau）积累。
对人类细胞模型进行E2处理并未影响Aβ分泌和pTau积累，但促进了神经元可塑性并减轻了星形胶质细胞增生样表型。E2的有限作用可能为E2临床试验的混合结果提供线索。
