Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells: Evidence that cleavage at the "β-secretase" site occurs in the Golgi apparatus

Gopal Thinakaran, David B. Teplow, Robert Siman, Barry Greenberg, Sangram S. Sisodiat

Research output: Contribution to journalArticle

Abstract

The 4-kDa β-amyloid peptide (Aβ), a principal component of parenchymal amyloid deposits in Alzheimer's disease, is derived from amyloid precursor proteins (APP). To identify potential intracellular compartments involved in Aβ production, we expressed human APP-695 (APPwt) and APP-695 harboring the Swedish double mutation (APPswe) associated with familial early-onset Alzheimer's disease, in mouse N2a cells. We demonstrate that cells expressing APPswe secrete high levels of Aβ peptides and β-secretase-generated soluble APP derivatives (APP) relative to cells expressing APPwt. In addition, we observed a concomitant diminution in the levels of α-secretase-generated soluble APP derivatives (APP). Our interpretation of these findings is that β-secretase cleavage occurs in an intracellular compartment and disables those substrates which would normally be cleaved by α-secretase. As anticipated, the levels of APPswe are diminished relative to the steadystate levels of surface-bound APPwt; moreover, surface-bound APPswe and APPwt molecules are released from the plasma membrane after cleavage by α-secretase, but not by β-secretase. Finally, by examining the rate of appearance of specific APP metabolites generated by β-secretase, we now unequivocally demonstrate that β-secretase cleavage of APPswe occurs within the Golgi apparatus, as early as the medial compartment.

Original languageEnglish (US)
Pages (from-to)9390-9397
Number of pages8
JournalJournal of Biological Chemistry
Volume271
Issue number16
DOIs
StatePublished - Apr 19 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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