O3–03–01: Presenilin–dependent transcriptional control of the Aβ–degrading enzyme neprilysin by AICD

Amyloid β–peptide (Aβ), which plays a central role in Alzheimer's disease, is generated by presenilin–dependent γ–secretase cleavage of β–amyloid precursor protein (βAPP). It is now believed that presenilin–dependent γ–secretase activity resides in a multimeric membrane–protein complex including presenilin (PS1 or PS2), nicastrin (Nct), aph–1 and pen–2. We have demonstrated that this presenilin–dependent γ–secretase activity also regulates Aβ degradation. Indeed, presenilin–deficient cells fail to degrade Aβ and have drastic reductions in the transcription, expression, and activity of neprilysin, a key Aβ–degrading enzyme. Neprilysin activity and expression are also drastically reduced in nicastrin–deficient cells, and lowered by γ–secretase inhibitors and by PS1/PS2 deficiency in mouse brain. In contrast, expressions of two other putative Aβ–degrading enzymes, endothelin–converting enzyme (ECE) and Insulin–degrading enzyme (IDE) are unchanged. We have reported that neprilysin activity and expression is restored in presenilin–deficient cells by transient expression of PS1 or PS2. Nicastrin also restores neprilysin activity and expression in nicastrin–deficient but not in presenilin–deficient fibroblasts, indicating that the control of neprilysin requires the completeness of the γ–secretase complex harboring its four reported components. Furthermore, we have clearly established that deficiency of βAPP, APLP1 or APLP2 drastically reduces neprilysin expression and activity in both fibroblasts and in brain tissues. We have also shown that neprilysin activity is restored by expression of the amyloid intracellular domain (AICD), which is cogenerated with Aβ, during γ–secretase cleavage of βAPP. Several lines of evidence indicate that the βAPP–binding proteins Fe65 and Tip60 stabilize AICD and favor its translocation to the nucleus. Our experiments have shown also that AICD translocates to the nucleus in the presence of Fe65 and Tip60 and the AICD–induced up–regulation of neprilysin is strongly potentiated by co–expression of AICD with Fe65 or Tip60. Finally we have demonstrated that neprilysin gene promoters are transactivated by AICDs from APP–like proteins (APP, APLP1, and APLP2), but not by Aβ or by the γ–secretase cleavage products of Notch, N– or E– cadherins. These results provide evidence that presenilin–dependent γ–secretase activity regulates neprilysin activity. In addition they support the hypothesis that AICD provides a physiological role within the nucleus to activate neprilysin gene transcription.

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