title: BACE1 activity is modulated by cell-associated sphingosine-1-phosphate.
abstract: 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.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Takasugi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Kunimichi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Satoko
authors.initials: S
authors.lastname: Osawa
authors.forename: Hayato
authors.initials: H
authors.lastname: Isshiki
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hori
authors.forename: Naoaki
authors.initials: N
authors.lastname: Shimada
authors.forename: Takuya
authors.initials: T
authors.lastname: Higo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yokoshima
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukuyama
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D013110:Sphingosine