Previously, we reported that the neurosteroid allopregnanolone (Allo) promoted neural stem cell regeneration, restored cognitive function, and reduced Alzheimer’s Disease (AD) pathology in the triple transgenic Alzheimer’s mouse model (3xTgAD). To investigate the underlying systems biology of Allo action in AD models in vivo, we assessed the regulation of Allo on the bioenergetic system of the brain. Outcomes of these analysis indicated that Allo significantly reversed deficits in mitochondrial respiration and biogenesis and key mitochondrial enzyme activity and reduced lipid peroxidation in the 3xTgAD mice in vivo. To explore the mechanisms by which Allo regulates the brain metabolism, we conducted targeted transcriptome analysis. These data further confirmed that Allo upregulated genes involved in glucose metabolism, mitochondrial bioenergetics, and signaling pathways while simultaneously downregulating genes involved in Alzheimer’s pathology, fatty acid metabolism, and mitochondrial uncoupling and dynamics. Upstream regulatory pathway analysis predicted that Allo induced peroxisome proliferator-activated receptor gamma (PPARG) and coactivator 1-alpha (PPARGC1A) pathways while simultaneously inhibiting the presenilin 1 (PSEN 1), phosphatase and tensin homolog (PTEN), and tumor necrosis factor (TNF) pathways to reduce AD pathology. Collectively, these data indicate that Allo functions as a systems biology regulator of bioenergetics, cholesterol homeostasis, and β-amyloid reduction in the brain. These systems are critical to neurological health, thus providing a plausible mechanistic rationale for Allo as a therapeutic to promote neural cell function and reduce the burden of AD pathology.

中文翻译：

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Allopregnanolone 可逆转雌性三重转基因阿尔茨海默病小鼠模型的生物能缺陷。


此前，我们报道了神经类固醇四氢孕酮 (Allo) 在三重转基因阿尔茨海默病小鼠模型 (3xTgAD) 中促进神经干细胞再生、恢复认知功能并减少阿尔茨海默病 (AD) 病理。为了研究 Allo 在 AD 模型体内作用的基础系统生物学，我们评估了 Allo 对大脑生物能系统的调节。这些分析结果表明，Allo 显着逆转了 3xTgAD 小鼠体内线粒体呼吸和生物发生以及关键线粒体酶活性的缺陷，并减少了脂质过氧化。为了探索 Allo 调节大脑代谢的机制，我们进行了有针对性的转录组分析。这些数据进一步证实，Allo 上调涉及葡萄糖代谢、线粒体生物能学和信号通路的基因，同时下调涉及阿尔茨海默病病理学、脂肪酸代谢、线粒体解偶联和动力学的基因。上游调控途径分析预测 Allo 诱导过氧化物酶体增殖物激活受体 γ (PPARG) 和共激活剂 1-α (PPARGC1A) 途径，同时抑制早老素 1 (PSEN 1)、磷酸酶和张力蛋白同源物 (PTEN) 和肿瘤坏死因子。 TNF）途径来减少 AD 病理。总的来说，这些数据表明 Allo 作为生物能量学、胆固醇稳态和大脑中 β-淀粉样蛋白减少的系统生物学调节剂。这些系统对神经健康至关重要，因此为 Allo 作为促进神经细胞功能和减轻 AD 病理负担的治疗方法提供了合理的机制原理。