The mechanism of γ-Secretase dysfunction in familial Alzheimer disease

The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid beta (A beta) 42 relative to A beta 40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair gamma-secretase and 'loss-of-function' mechanisms have also been postulated. Here, we use kinetic studies to demonstrate that FAD mutations affect A beta generation via three different mechanisms, resulting in qualitative changes in the A beta profiles, which are not limited to A beta 42. Loss of epsilon-cleavage function is not generally observed among FAD mutants. On the other hand, gamma-secretase inhibitors used in the clinic appear to block the initial epsilon-cleavage step, but unexpectedly affect more selectively Notch than APP processing, while modulators act as activators of the carboxypeptidase-like (gamma) activity. Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the A beta products, and suggest fundamental improvements for current drug development efforts. The EMBO Journal (2012) 31, 2261-2274. doi: 10.1038/emboj.2012.79; Published online 13 April 2012