Destruxin E decreases Beta-amyloid generation by reducing colocalization of beta-amyloid-cleaving enzyme 1 and beta-amyloid protein precursor.
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.
Itoh
Naohiro
N
Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Okochi
Masayasu
M
Tagami
Shinji
S
Nishitomi
Kouhei
K
Nakayama
Taisuke
T
Yanagida
Kanta
K
Fukumori
Akio
A
Jiang
Jingwei
J
Mori
Kohji
K
Hosono
Motoko
M
Kikuchi
Jyunko
J
Nakano
Yuko
Y
Takinami
Yoshihiko
Y
Dohi
Keiji
K
Nishigaki
Atsuko
A
Takemoto
Hiroshi
H
Minagawa
Kazuyuki
K
Katoh
Takaaki
T
Willem
Michael
M
Haass
Christian
C
Morihara
Takashi
T
Tanaka
Toshihisa
T
Kudo
Takashi
T
Hasegawa
Hiroshi
H
Nishimura
Masaki
M
Sakaguchi
Gaku
G
Kato
Akira
A
Takeda
Masatoshi
M
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
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