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Li, J. et al.

Li, Fici, Mao, Myers, Shuang, Donoho, Pauley, Himes, Qin, Kola, Merchant, Nye,

Positive and negative regulation of the gamma-secretase activity by nicastrin in a murine model.

Nicastrin is a component of the gamma-secretase complex that has been shown to adhere to presenilin-1 ( PS1), Notch, and APP. Here we demonstrate that Nicastrin-deficient mice showed a phenotype that is indistinguishable from PS1/ PS2 double knock-out mice, whereas heterozygotes were healthy and viable. Fibroblasts derived from Nicastrin-deficient embryos were unable to generate amyloid beta-peptide and failed to release the intracellular domain of APP- or Notch1-Gal4-VP16 fusion proteins. Additionally, C- and N-terminal fragments of PS1 and the C-terminal fragments of PS2 were not detectable in Nicastrin-null fibroblasts, whereas full-length PS1 accumulated in null fibroblasts, indicating that Nicastrin is required for the endoproteolytic processing of presenilins. Interestingly, cells derived from Nicastrin heterozygotes produced relatively higher levels of amyloid beta-peptide whether the source was endogenous mouse or transfected human APP. These data demonstrate that Nicastrin is essential for the gamma-secretase cleavage of APP and Notch in mammalian cells and that Nicastrin has both positive and negative functions in the regulation of gamma-secretase activity.[1]

References

Positive and negative regulation of the gamma-secretase activity by nicastrin in a murine model. Li, J., Fici, G.J., Mao, C.A., Myers, R.L., Shuang, R., Donoho, G.P., Pauley, A.M., Himes, C.S., Qin, W., Kola, I., Merchant, K.M., Nye, J.S. J. Biol. Chem. (2003) [Pubmed]

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