Secretases as therapeutic targets for the treatment of Alzheimer's disease.

The extracellular deposition of short amyloid peptides in the brain of patients is thought to be a central event in the pathogenesis of Alzheimer's Disease. The generation of the amyloid peptide occurs via a regulated cascade of cleavage events in its precursor protein, A beta PP. At least three enzymes are responsible for A beta PP proteolysis and have been tentatively named alpha-, beta- and gamma-secretases. The recent identification of several of these secretases is a major leap in the understanding how these secretases regulate amyloid peptide formation. Members of the ADAM family of metalloproteases are involved in the non-amyloidogenic alpha-secretase pathway. The amyloidogenic counterpart pathway is initiated by the recently cloned novel aspartate protease named BACE. The available data are conclusive and crown BACE as the long-sought beta-secretase. This enzyme is a prime candidate drug target for the development of therapy aiming to lower the amyloid burden in the disease. Finally, the gamma-secretases are intimately linked to the function of the presenilins. These multi-transmembrane domain proteins remain intriguing study objects. The hypothesis that the presenilins constitute a complete novel type of protease family, and are cleaving A beta PP within the transmembrane region, remains an issue of debate. Several questions remain unanswered and direct proof that they exert catalytic activity is still lacking. The subcellular localization of presenilins in neurons, their integration in functional multiprotein complexes and the recent identification of additional modulators of gamma-secretase, like nicastrin, indicate already that several players are involved. Nevertheless, the rapidly increasing knowledge in this area is already paving the road towards selective inhibitors of this secretase as well. It is hoped that such drugs, possibly in concert with the experimental vaccination therapies that are currently tested, will lead to a cure of this inexorable disease.