The AD community’s overwhelming focus on β and γ-secretase has all but obscured a third enzyme that clips APP in an alternative, altogether more benign pathway. This ugly duckling is, of course, α-secretase. It has been snubbed partly because, unlike both β- and γ-secretase, its unique identity has remained stubbornly elusive, and partly because conventional wisdom holds that blocking a target enzyme is easier than boosting it, which is what a therapeutic strategy based on α-secretase would have to do. Despite all this, α-secretase fairly looks the part of a swan in a paper in the current issue of the Journal of Clinical Investigation.
Rolf Postina and Falk Fahrenholz at the University of Mainz in Germany, with colleagues there and in Belgium, present the first in-vivo evidence that manipulating the activity of one of the three major physiological α-secretase candidates—the disintegrin and metalloproteinase ADAM-10—can improve standard AD markers in a mouse model. In a clever experiment, the authors made mice that mildly over-express ADAM-10 in neurons and then bred them to transgenic mice that over-express, also in neurons, the APPV717I London mutation. They found that the double-transgenic progeny not only overproduced the requisite APPsα fragment (which is known to be neurotrophic), but also escaped the amyloid deposition and memory deficits that mark the APPV717I single-transgenic mice. Aβ reduction was moderately reduced in the double-transgenics.
This is interesting for several reasons, not least because the subtle ADAM-10 overexpression models the action of any future anti-amyloid drug on a secretase target more realistically than do more standard BACE or γ-secretase knockout experiments. The Postina et al. paper, along with a commentary by Stephan Lichtenthaler and Christian Haass discussing the therapeutic potential of promoting α-secretase cleavage, both are available in full online.—Gabrielle Strobel
No Available Further Reading
- Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, Van Leuven F, Fahrenholz F. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest. 2004 May;113(10):1456-64. PubMed.