Background

Estrogen deficiency causes mitochondrial defects that precede pathological changes related to Alzheimer's disease (AD) in the mouse model of postmenopause. The aim of this study was to investigate in such a mouse model whether and how estrogen receptor β (ERβ) was involved in prevention of mitochondrial damage and protection of neurons in the hippocampus.

Methods

A mouse model of postmenopausal AD was created by ovariectomizing female 3xTg-AD mice, some of which were subcutaneously injected for six weeks with the non-steroidal ERβ agonist diarylpropionitrile. ERβ expression in female C57BL/6J mice was knocked down using shRNA interference. The different groups of animals were compared in terms of cognitive function using the Y-maze test, new object recognition test, and Morris water maze test, expression of numerous proteins related to mitochondrial biogenesis, mitophagy, apoptosis, and mitochondrial membrane potential, as well as deposition of amyloid β and neurofibrillary tangles. To complement these in vivo studies, we probed the effects of diarylpropionitrile on ERβ expression, apoptosis, and mitochondrial homeostasis in primary rat hippocampal neurons treated with amyloid β.

Results

ERβ knockdown in C57BL/6J mice produced cognitive impairment, reduced mitochondrial biogenesis by downregulating PGC-1α, NRF1, mtTFA, and TOM20, and decreased mitophagy by downregulating Pink1, Parkin, and LC3B while upregulating PARIS and p62. ERβ knockdown promoted neuronal apoptosis by upregulating Cleaved-Caspase 9, Cleaved-Caspase 3, and Bax, while downregulating Bcl2 in hippocampus. Diarylpropionitrile mitigated cognitive decline in ovariectomized 3xTg-AD mice, which was associated with downregulation of BACE1, reduction of Aβ deposition, neurofibrillary tangles, and tau hyperphosphorylation, and upregulation of ERβ, increases in mitochondrial biogenesis and mitophagy, and decreases in apoptosis. The effects of diarylpropionitrile in mice were recapitulated in Aβ-injured primary rat hippocampal neurons.

Conclusions

ERβ activation can support learning and memory and alleviate AD symptoms in the postmenopausal AD model, which may involve regulation of neuronal mitochondrial biogenesis and mitophagy via NRF1/PGC-1α. This study supports further research on ERβ as a therapeutic target for postmenopausal women with AD.

中文翻译：

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雌激素受体β通过 NRF1/PGC-1α 微调线粒体稳态发挥神经保护作用

 背景

雌激素缺乏会导致线粒体缺陷，这些缺陷先于绝经后小鼠模型中与阿尔茨海默病 （AD） 相关的病理变化。本研究的目的是在这样的小鼠模型中研究雌激素受体β （ERβ） 是否以及如何参与预防线粒体损伤和保护海马神经元。

 方法

通过对雌性 3xTg-AD 小鼠进行卵巢切除来创建绝经后 AD 小鼠模型，其中一些小鼠皮下注射非甾体 ERβ 激动剂二芳基丙腈 6 周。使用 shRNA 干扰敲低雌性 C57BL/6J 小鼠中 ERβ 的表达。使用 Y 迷宫试验、新物体识别试验和 Morris 水迷宫试验比较不同动物组的认知功能，与线粒体生物发生、线粒体自噬、细胞凋亡和线粒体膜电位相关的多种蛋白质的表达，以及淀粉样蛋白β沉积和神经原纤维缠结。为了补充这些体内研究，我们探讨了二芳基丙腈对用淀粉样蛋白 β 处理的原代大鼠海马神经元中 ERβ 表达、细胞凋亡和线粒体稳态的影响。

 结果

C57BL/6J 小鼠的 ERβ 敲低产生认知障碍，通过下调 PGC-1α 、 NRF1 、 mtTFA 和 TOM20 减少线粒体生物发生，通过下调 Pink1 、 Parkin 和 LC3B 减少线粒体自噬，同时上调 PARIS 和 p62。ERβ 敲除通过上调 Cleaved-Caspase 9、Cleaved-Caspase 3 和 Bax 促进神经元凋亡，同时下调海马中的 Bcl2。Diarylpropionitrile 减轻了卵巢切除的 3xTg-AD 小鼠的认知能力下降，这与 BACE1 的下调、Aβ 沉积的减少、神经原纤维缠结和 tau 过度磷酸化以及 ERβ 的上调、线粒体生物发生和线粒体自噬的增加以及细胞凋亡的减少有关。在 Aβ 损伤的原代大鼠海马神经元中概括了二芳基丙腈对小鼠的影响。

 结论

ERβ 激活可以支持学习和记忆并缓解绝经后 AD 模型中的 AD 症状，这可能涉及通过 NRF1/PGC-1α 调节神经元线粒体生物发生和线粒体自噬。本研究支持进一步研究 ERβ 作为绝经后 AD 妇女的治疗靶点。