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 (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