title: Destruxin E decreases Beta-amyloid generation by reducing colocalization of beta-amyloid-cleaving enzyme 1 and beta-amyloid protein precursor.
abstract: Alzheimer-disease-associated beta-amyloid (Abeta) is produced by sequential endoproteolysis of beta-amyloid protein precursor (betaAPP): the extracellular portion is shed by cleavage in the juxtamembrane region by beta-amyloid-cleaving enzyme (BACE)/beta-secretase, after which it is cleaved by presenilin (PS)/gamma-secretase near the middle of the transmembrane domain. Thus, inhibition of either of the secretases reduces Abeta generation and is a fundamental strategy for the development of drugs to prevent Alzheimer disease. However, it is not clear how small compounds reduce Abeta production without inhibition of the secretases. Such compounds are expected to avoid some of the side effects of secretase inhibitors. Here, we report that destruxin E (Dx-E), a natural cyclic hexadepsipeptide, reduces Abeta generation without affecting BACE or PS/gamma-secretase activity. In agreement with this, Dx-E did not inhibit Notch signaling. We found that Dx-E decreases colocalization of BACE1 and betaAPP, which reduces beta-cleavage of betaAPP. Therefore, the data demonstrate that Dx-E represents a novel Abeta-reducing process which could have fewer side effects than secretase inhibitors.
authors.affiliation: Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Itoh
authors.forename: Masayasu
authors.initials: M
authors.lastname: Okochi
authors.forename: Shinji
authors.initials: S
authors.lastname: Tagami
authors.forename: Kouhei
authors.initials: K
authors.lastname: Nishitomi
authors.forename: Taisuke
authors.initials: T
authors.lastname: Nakayama
authors.forename: Kanta
authors.initials: K
authors.lastname: Yanagida
authors.forename: Akio
authors.initials: A
authors.lastname: Fukumori
authors.forename: Jingwei
authors.initials: J
authors.lastname: Jiang
authors.forename: Kohji
authors.initials: K
authors.lastname: Mori
authors.forename: Motoko
authors.initials: M
authors.lastname: Hosono
authors.forename: Jyunko
authors.initials: J
authors.lastname: Kikuchi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakano
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Takinami
authors.forename: Keiji
authors.initials: K
authors.lastname: Dohi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nishigaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemoto
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Minagawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Katoh
authors.forename: Michael
authors.initials: M
authors.lastname: Willem
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Takashi
authors.initials: T
authors.lastname: Morihara
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D047630:Depsipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005656:Fungal Proteins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053764:Presenilin-1 / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D016564:Amyloid beta-Protein Precursor; D047630:Depsipeptides; D005656:Fungal Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; C040425:destruxin E