Clarification of the mechanism underlying y-secretase cleavage by presenilin complexes

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Presenilins, causative molecules for familial Alzheimer's disease (FAD), are required for y-secretase activity. y- Secretase mediates intramembrane cleavage of amyloid precursor protein (APP), resulting in generation of pathogenic peptides named amyloid β(Aβ). The clarification of this mechanism is a central issue in AD research, because the longer Aβ ending at residue 42 or 43 (Aβ_<42/3>) are thought to play a critical role in the pathogenesis of AD. We have revealed that presenilins mediate y-secretase cleavage of APP and Notch by forming macromolecular complexes together with nicastrin and other proteins (Nat Cell Biol, 2001), and that another component PEN-2 enhances the accessibility of the y-secretase substrates (J Neurochem, 2004). FAD- causing mutations in the presenilins increase production of longer Aβ_<42/43> by altering y-secretase activity, although the underlying mechanism remains unknown. Using a random mutagenesis screen of presenilin 1 (PS1), we identified five unique mutants including R278I-PS1 and L435H-PS1, which exclusively generated a high level of Aβ_<43> but that did not support physiological PS1 endoproteolysis or Aβ_<40> generation (J Biol Chem, 2005). Cell biological investigation and pharmacological study using the inhibitors suggest that the effects of PS1 mutations and y-secretase inhibitors on the specificity are commonly mediated through a conformational change in the complex. Our results suggest that small molecules could be designed to induce alternate PS complex conformations that are more favourable to the generation of Aβ_<40> rather than pathogenic Aβ_<42/43>. Additionally, we reported that presenilins exert a pro-apoptotic effect by binding to FKBP38 and reducing anti- apoptotic Bcl-2 in the mitochondria. Furthermore, FAD mutations of presenilins enhance this pro-apoptotic activity, sensitizing neurons to apoptotic stimuli in brains (Hum Mol Genet, in press).