Dissociated phenotypes in presenilin transgenic mice define functionally distinct &#x03B3-secretases.

&#x03B3-secretase depends on presence of presenilins (PS), Nct, Aph-I, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-β precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PSI or P52 genes shift APP cleavage from production of amyloid-β (Aβ) 40 peptide to greater production of Aβ42. Although studies in PSI/PS2-deficient embryonic cells define overlapping activities for these proteins. in vivo complementation of PSI-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PSI transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Aβ40 or Aβ42 production. and FAD PS2 alleles support robust production of only Aβ42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a "gained" competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against &#x03B3-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct &#x03B3-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates. [ABSTRACT FROM AUTHOR]