Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.
J Alzheimers Dis. 2022;85(4):1529-1544. doi: 10.3233/JAD-215205.
Sphingosine 1-phosphate (S1P) and ceramides have been implicated in the development of Alzheimer's disease. Apolipoprotein E (ApoE) isoforms are also involved in the development of Alzheimer's disease.
We aimed at elucidating the potential association of the ApoE isoforms with sphingolipid metabolism in the central nervous system.
We investigated the modulations of apolipoprotein M (apoM), a carrier of S1P, S1P, and ceramides in Apoeshl mice, which spontaneously lack apoE, and U251 cells and SH-SY5Y cells infected with adenovirus vectors encoding for apoE2, apoE3, and apoE4.
In the brains of Apoeshl mice, the levels of apoM were lower, while those of ceramides were higher. In U251 cells, cellular apoM and S1P levels were the highest in the cells overexpressing apoE2 among the apoE isoforms. The cellular and medium contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 and increased in the cells overexpressing apoE4. In SH-SY5Y cells, apoM mRNA and medium S1P levels were also the highest in the cells overexpressing apoE2. The cellular contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 = apoE4 and those in medium decreased in the order of the cells overexpressing apoE3 > apoE2, while increased in the cells overexpressing apoE4.
The modulation of apoM and S1P might partly explain the protective effects of apoE2 against Alzheimer's disease, and the modulation of ceramides might be one of the mechanisms explaining the association of apoE4 with the development of Alzheimer's disease.
神经酰胺和鞘氨醇 1-磷酸 (S1P) 已被认为与阿尔茨海默病的发展有关。载脂蛋白 E (ApoE) 异构体也参与了阿尔茨海默病的发展。
我们旨在阐明 ApoE 异构体与中枢神经系统中鞘脂代谢的潜在关联。
我们研究了载脂蛋白 M (apoM) 的调节作用，apoM 是 S1P 的载体，在自发性缺乏 apoE 的 Apoeshl 小鼠、感染载有 apoE2、apoE3 和 apoE4 的腺病毒载体的 U251 细胞和 SH-SY5Y 细胞中，S1P 和神经酰胺的水平。
在 Apoeshl 小鼠的大脑中，apoM 的水平较低，而神经酰胺的水平较高。在 U251 细胞中，apoE 异构体中，apoE2 过表达的细胞中 apoM 和 S1P 的细胞和培养基水平最高。过表达 apoE3 的细胞中的细胞和培养基中的神经酰胺含量减少，而过表达 apoE4 的细胞中的神经酰胺含量增加。在 SH-SY5Y 细胞中，apoE2 过表达的细胞中 apoM mRNA 和培养基中 S1P 水平也最高。过表达 apoE3 的细胞中的细胞神经酰胺含量减少，而过表达 apoE2 和 apoE4 的细胞中的细胞神经酰胺含量减少，而培养基中的细胞神经酰胺含量减少，而过表达 apoE3 的细胞中的培养基神经酰胺含量减少，而过表达 apoE4 的细胞中的培养基神经酰胺含量增加。
apoM 和 S1P 的调节可能部分解释了 apoE2 对阿尔茨海默病的保护作用，而神经酰胺的调节可能是解释 apoE4 与阿尔茨海默病发展相关的机制之一。
