BACE1 Activity Is Modulated by Cell-Associated Sphingosine-1-Phosphate

作者：Takasugi Nobumasa; Sasaki Tomoki; Suzuki Kunimichi; Osawa Satoko; Isshiki Hayato; Hori Yukiko; Shimada Naoaki; Higo Takuya; Yokoshima Satoshi; Fukuyama Tohru; Lee Virginia M Y; Trojanowski John Q; Tomita Taisuke^*; Iwatsubo Takeshi

来源：Journal of Neuroscience, 2011, 31(18): 6850-6857.

DOI：10.1523/JNEUROSCI.6467-10.2011

Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of beta-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-beta peptide (A beta) production, is modulated by S1P in mouse neurons. Treatment by SphK inhibitor, RNA interference knockdown of SphK, or overexpression of S1P degrading enzymes decreased BACE1 activity, which reduced A beta production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer's disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer's disease.

• 出版日期2011-5-4