Glycosylphosphatidylinositol-anchored proteins play an important role in the biogenesis of the Alzheimer's amyloid β-protein

Kumar Sambamurti, Daniel Sevlever, Thillai Koothan, Lawrence M. Refolo, Inga Pinnix, Swetal Gandhi, Luisa Onstead, Linda Younkin, Christian M. Prada, Debra Yager, Yasumasa Ohyagi, Christopher B. Eckman, Terrone L. Rosenberry, Steven G. Younkin

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44 Scopus citations


The Alzheimer's amyloid protein (Aβ) is released from the larger amyloid β-protein precursor (APP) by unidentified enzymes referred to as β- and γ-secretase, β-Secretase cleaves APP on the amino side of Aβ producing a large secreted derivative (sAPPβ) and an Aβ-bearing C-terminal derivative that is subsequently cleaved by γ-secretase to release Aβ. Alternative cleavage of the APP by α-secretase at Aβ16/17 releases the secreted derivative sAPPα. In yeast, α-secretase activity has been attributed to glycosylphosphatidylinositol (GPI)-anchored aspartyl proteases. To examine the role of GPI-anchored proteins, we specifically removed these proteins from the surface of mammalian cells using phosphatidylinositol-specific phospholipase C (PI-PLC). PI-PLC treatment of fetal guinea pig brain cultures substantially reduced the amount of Aβ40 and Aβ42 in the medium but had no effect on sAPPα. A mutant CHO cell line (gpi85), which lacks GPI-anchored proteins, secreted lower levels of Aβ40, Aβ42, and sAPPβ than its parental line (GPI+). When this parental line was treated with PI-PLC, Aβ40, Aβ42, and sAPPβ decreased to levels similar to those observed in the mutant line, and the mutant line was resistant to these effects of PI-PLC. These findings provide strong evidence that one or more GPI-anchored proteins play an important role in β-secretase activity and Aβ secretion in mammalian cells. The cell-surface GPI-anchored protein(s) involved in Aβ biogenesis may be excellent therapeutic target(s) in Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)26810-26814
Number of pages5
JournalJournal of Biological Chemistry
Issue number38
StatePublished - Sep 17 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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