The non-amyloidogenic pathway: structure and function of alpha-secretases.

The amyloid cascade hypothesis is the most accepted explanation for the pathogenesis of Alzheimer's disease (AD). APP is the precursor of the amyloid beta peptide (Abeta), the principal proteinaceous component of amyloid plaques in brains of Alzheimer's disease patients. Proteolytic cleavage of APP by the alpha-secretase within the Abeta sequence precludes formation of amyloidogenic peptides and leads to a release of soluble APPsalpha which has neuroprotective properties. In several studies, a decreased amount of APPsalpha in the cerebrospinal fluid of AD patients has been observed. Three members of the ADAM family (a disintegrin and metalloproteinase) ADAM-10, ADAM-17 (TACE) and ADAM-9 have been proposed as alpha-secretases. We review the evidence for each of these enzymes acting as a physiologically relevant alpha-secretase. In particular, we focus on ADAM-10, which recently was shown in a transgenic mouse model for AD, to act as an alpha-secretase in vivo. We also discuss the pharmacological up-regulation of alpha-secretases as a possible therapeutic treatment for AD.