TY - JOUR
T1 - BACE1 activity is modulated by cell-associated sphingosine-1-phosphate
AU - Takasugi, Nobumasa
AU - Sasaki, Tomoki
AU - Suzuki, Kunimichi
AU - Osawa, Satoko
AU - Isshiki, Hayato
AU - Hori, Yukiko
AU - Shimada, Naoaki
AU - Higo, Takuya
AU - Yokoshima, Satoshi
AU - Fukuyama, Tohru
AU - Lee, Virginia M.Y.
AU - Trojanowski, John Q.
AU - Tomita, Taisuke
AU - Iwatsubo, Takeshi
PY - 2011/5/4
Y1 - 2011/5/4
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
AB - 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
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U2 - 10.1523/JNEUROSCI.6467-10.2011
DO - 10.1523/JNEUROSCI.6467-10.2011
M3 - Article
C2 - 21543615
AN - SCOPUS:79955770841
SN - 0270-6474
VL - 31
SP - 6850
EP - 6857
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 18
ER -