Itoh, Naohiro; Okochi, Masayasu; Tagami, Shinji; Nishitomi, Kouhei; Nakayama, Taisuke; Yanagida, Kanta; Fukumori, Akio; Jiang, Jingwei; Mori, Kohji; Hosono, Motoko; Kikuchi, Jyunko; Nakano, Yuko; Takinami, Yoshihiko; Dohi, Keiji; Nishigaki, Atsuko; Takemoto, Hiroshi; Minagawa, Kazuyuki; Katoh, Takaaki; Willem, Michael; Haass, Christian; Morihara, Takashi; Tanaka, Toshihisa; Kudo, Takashi; Hasegawa, Hiroshi; Nishimura, Masaki; Sakaguchi, Gaku; Kato, Akira; Takeda, Masatoshi
Destruxin E Decreases Beta-Amyloid Generation by Reducing Colocalization of Beta-Amyloid-Cleaving Enzyme 1 and Beta-Amyloid Protein Precursor.
In: Neurodegenerative Diseases, Nr. 5-6: S. 230-239
Alzheimer-disease-associated beta-amyloid (A beta) is produced by sequential endoproteolysis of beta-amyloid protein precursor (beta APP): 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 A beta generation and is a fundamental strategy for the development of drugs to prevent Alzheimer disease. However, it is not clear how small compounds reduce A beta 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 A beta 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 beta APP, which reduces beta-cleavage of beta APP. Therefore, the data demonstrate that Dx-E represents a novel A beta-reducing process which could have fewer side effects than secretase inhibitors. Copyright (C) 2009 S. Karger AG, Basel