Overexpression of nicastrin increases Abeta production.

M. Paul Murphy, Pritam Das, Andrew C. Nyborg, Marjorie J. Rochette, Mark W. Dodson, Nicole M. Loosbrock, Terrance M. Souder, Chris McLendon, Sami L. Merit, Siân C. Piper, Karen R. Jansen, Todd E. Golde

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Gamma-secretase cleavage is the final proteolytic step that releases the amyloid beta-peptide (Abeta) from the amyloid beta-protein precursor (APP). Significant evidence indicates that the presenilins (PS) are catalytic components of a high molecular weight gamma-secretase complex. The glycoprotein nicastrin was recently identified as a functional unit of this complex based on 1) binding to PS and 2) the ability to modulate Abeta production following mutation of a conserved DYIGS region. In contrast to the initial report, we find that overexpression of wild-type (WT) nicastrin increases Abeta production, whereas DYIGS mutations (MT) have little or no effect. The increase in Abeta production is associated with an increase in gamma-secretase activity but not with a detectable increase in PS1 levels. Subcellular fractionation studies show that WT but not MT nicastrin matures into buoyant membrane fractions enriched in gamma-secretase activity. These data support the hypothesis that nicastrin is an essential component of the gamma-secretase complex. The finding that WT nicastrin overexpression can increase gamma-secretase activity without altering levels of the presumed catalytic component (PS) of the enzyme may point to a role for nicastrin in facilitating cleavage by regulating substrate interactions with the gamma-secretase complex.

Original languageEnglish
Pages (from-to)1138-1140
Number of pages3
JournalFASEB Journal
Issue number9
StatePublished - Jun 2003

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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