Enhanced production and oligomerization of the 42-residue amyloid β- protein by chinese hamster ovary cells stably expressing mutant presenilins

Weiming Xia, Jimin Zhang, Dora Kholodenko, Martin Citron, Marcia B. Podlisny, David B. Teplow, Christian Haass, Peter Seubert, Edward H. Koo, Dennis J. Selkoe

Research output: Contribution to journalArticle

265 Scopus citations

Abstract

Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes cause the most common and aggressive form of early onset familial Alzheimer's disease. To elucidate their pathogenic mechanism, wild-type (wt) or mutant (M146L, C410Y) PS1 and wt or mutant (M239V) PS2 genes were stably transfected into Chinese hamster ovary cells that overexpress the β-amyloid precursor protein (APP). The identity of the 43-45-kDa PSI holoproteins was confirmed by N-terminal radiosequencing. PSI was rapidly processed (t(1/2) = 40 min) in the endoplasmic reticulum into stable fragments. Wild-type and mutant PS2 holoproteins exhibited similar half lives (1.5 h); however, their endoproteolytic fragments showed both mutation-specific and cell type- specific differences. Mutant PS1 or PS2 consistently induced a 1.4-2.5-fold increase (p < 0.001) in the relative production of the highly amyloidogenic 42-residue form of amyloid β-protein (Aβ42) as determined by quantitative immunoprecipitation and by enzyme-linked immunosorbent assay. In mutant PS1 and PS2 cell lines with high increases in Aβ42/Aβ(total) ratios, spontaneous formation of low molecular weight oligomers of Aβ42 was observed in media, suggesting enhanced Aβ aggregation from the elevation of Aβ42. We conclude that mutant PS1 and PS2 proteins enhance the proteolysis of β-amyloid precursor protein by the γ-secretase cleaving at Aβ residue 42, thereby promoting amyloidogenesis.

Original languageEnglish (US)
Pages (from-to)7977-7982
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number12
DOIs
StatePublished - 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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