TY - JOUR T1 - BACE1 Activity Is Modulated by Cell-Associated Sphingosine-1-Phosphate JF - The Journal of Neuroscience JO - J. Neurosci. SP - 6850 LP - 6857 DO - 10.1523/JNEUROSCI.6467-10.2011 VL - 31 IS - 18 AU - Nobumasa Takasugi AU - Tomoki Sasaki AU - Kunimichi Suzuki AU - Satoko Osawa AU - Hayato Isshiki AU - Yukiko Hori AU - Naoaki Shimada AU - Takuya Higo AU - Satoshi Yokoshima AU - Tohru Fukuyama AU - Virginia M.-Y. Lee AU - John Q. Trojanowski AU - Taisuke Tomita AU - Takeshi Iwatsubo Y1 - 2011/05/04 UR - http://www.jneurosci.org/content/31/18/6850.abstract N2 - 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 β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-β peptide (Aβ) 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 Aβ 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. ER -