β-羟丁酸通过hnRNP A1调控Oct4抑制星形胶质细胞衰老影响AD的发生

The functions of astrocytes (AS) are closely related to the pathological process of Alzheimer’s disease (AD). It is reported that amyloid β-protein (Aβ) induces the senescence of AS, while β-hydroxybutyrate (β-HB) inhibits cell senescence, as well as protects the central nervous system. However, it is unclear whether β-HB improves the intracerebral environment by inhibiting the senescence of AS, furthermore inhibiting the pathological process of AD. Previous studies showed that the blood β-HB level in mice is positively correlated to Oct4 expression. Our studies also indicated that β-HB up-regulated Oct4 expression level, as well as down-regulated the expression of inflammatory factors in mice cortex. Activation of Oct4 can inhibit cell senescence and improve the inflammatory environment, while hnRNP A1 regulates the expression of Oct4. Basing on the researches above, we propose the following scientific hypotheses: β-HB can inhibit AS senescence induced by Aβ; β-HB can up-regulate the expression of Oct4 in AS through interaction with hnRNP A1; the expression of Oct4 can inhibit the senescence of AS, improving the intracerebral environment thus inhibiting the occurrence and development of AD. This study will provide theoretical and experimental basis for the treatment and prevention of AD.

星形胶质细胞（AS细胞）的功能与阿尔茨海默病（AD）的病理进程密切相关。研究发现，β-淀粉样蛋白（Aβ）可诱导AS细胞的衰老，而β-羟丁酸（β-HB）能抑制细胞衰老，具有中枢神经系统保护作用，然而β-HB能否通过抑制AS细胞衰老从而改善脑内内环境，抑制AD的病理进程尚不清楚。已有的研究表明，小鼠血液β-HB的含量与干细胞因子Oct4的表达量成正相关。我们发现β-HB能够激活小鼠皮层Oct4表达，抑制炎症因子的表达。Oct4的激活有助于抑制细胞衰老，改善炎症环境，而核不均一核糖核蛋白A1（hnRNP A1）能够调控Oct4的表达。基于以上研究，我们提出：β-HB可以抑制Aβ诱导的AS细胞衰老；β-HB可以通过与hnRNP A1相互作用上调AS细胞Oct4的表达；Oct4的表达可以抑制AS细胞的衰老，从而改善脑内内环境，抑制AD的发生和发展。本研究将为AD的治疗、尤其是预防提供理论和实验依据。

阿尔茨海默病（AD）是一种年龄相关的神经退行性疾病，表现为不可逆的大脑损伤和认知功能障碍。β-羟丁酸作为一种大脑的替代能源，同时具有神经保护作用，但是β-羟丁酸缓解AD病理进程的具体机制尚不明确。本研究通过含酮饮食干预转基因AD小鼠，发现β-羟丁酸能够改善AD小鼠的认知水平，提高血浆β-羟丁酸的含量，系统性地影响衰老表型，减少小鼠海马区域β-淀粉样斑块的沉积。通过对海马组织的转录组测序分析发现，β-羟丁酸下调了一些促炎因子和信号通路的表达，改善了脑内炎症情况。通过对小鼠粪便样本的16s rDNA扩增子测序，构建了小鼠肠道微生物表达谱。通过在原代星形胶质细胞的研究发现，β-羟丁酸能够一定程度上抑制β-淀粉样蛋白诱导的星形胶质细胞衰老。此外，我们发现，β-羟丁酸能够引起海马组织、肝脏组织及原代星形胶质细胞的β-羟丁酰化。本研究能够为AD的治疗，尤其是预防提供理论和实验依据。

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