Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita, Okayama, Japan; Research Fellow of Japan Society for the Promotion of Science, Chiyoda, Tokyo, Japan.
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita, Okayama, Japan.
J Lipid Res. 2024 Mar;65(3):100510. doi: 10.1016/j.jlr.2024.100510. Epub 2024 Jan 26.
The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of apolipoprotein E (ApoE), a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid β (Aβ)-metabolizing effects, the nuclear receptors, retinoid X receptor (RXR) and LXR, which are involved in ApoE expression, are considered promising therapeutic targets for AD. However, the therapeutic effects of agents targeting these receptors are limited or vary considerably among groups, indicating the involvement of an unknown pathological factor that modifies astrocyte and ApoE function. Here, we focused on the signaling lipid, sphingosine-1-phosphate (S1P), which is mainly produced by sphingosine kinase 2 (SphK2) in the brain. Using astrocyte models, we found that upregulation of SphK2/S1P signaling suppressed ApoE induction by both RXR and LXR agonists. We also found that SphK2 activation reduced RXR binding to the APOE promoter region in the nucleus, suggesting the nuclear function of SphK2/S1P. Intriguingly, suppression of SphK2 activity by RNA knockdown or specific inhibitors upregulated lipidated ApoE induction. Furthermore, the induced ApoE facilitates Aβ uptake in astrocytes. Together with our previous findings that SphK2 activity is upregulated in AD brain and promotes Aβ production in neurons, these results indicate that SphK2/S1P signaling is a promising multifunctional therapeutic target for AD that can modulate astrocyte function by stabilizing the effects of RXR and LXR agonists, and simultaneously regulate neuronal pathogenesis.
星形胶质细胞功能变化与阿尔茨海默病（AD）病理进展之间的联系引起了广泛关注。有趣的是，AD 中活化的星形胶质细胞表现出脂质含量和代谢的异常。特别是，脂质转运蛋白载脂蛋白 E（ApoE）的表达降低。由于 ApoE 具有抗炎和淀粉样β（Aβ）代谢作用，因此参与 ApoE 表达的核受体视黄醇 X 受体（RXR）和肝X 受体（LXR）被认为是 AD 的有希望的治疗靶点。然而，针对这些受体的药物的治疗效果有限，或者在不同群体中差异很大，这表明存在一种未知的病理因素改变了星形胶质细胞和 ApoE 的功能。在这里，我们重点研究了信号脂质——鞘氨醇-1-磷酸（S1P），它主要由脑内的鞘氨醇激酶 2（SphK2）产生。使用星形胶质细胞模型，我们发现上调 SphK2/S1P 信号抑制了 RXR 和 LXR 激动剂诱导的 ApoE 诱导。我们还发现 SphK2 激活降低了 RXR 与核内 APOE 启动子区域的结合，提示 SphK2/S1P 的核功能。有趣的是，通过 RNA 敲低或特异性抑制剂抑制 SphK2 活性可上调脂化 ApoE 的诱导。此外，诱导的 ApoE 促进星形胶质细胞摄取 Aβ。结合我们之前的研究结果，即 SphK2 活性在 AD 脑中上调并促进神经元中 Aβ的产生，这些结果表明 SphK2/S1P 信号是 AD 的有前途的多功能治疗靶点，通过稳定 RXR 和 LXR 激动剂的作用调节星形胶质细胞功能，同时调节神经元发病机制。
