TY - JOUR
T1 - Glycosylphosphatidylinositol-anchored proteins play an important role in the biogenesis of the Alzheimer's amyloid β-protein
AU - Sambamurti, Kumar
AU - Sevlever, Daniel
AU - Koothan, Thillai
AU - Refolo, Lawrence M.
AU - Pinnix, Inga
AU - Gandhi, Swetal
AU - Onstead, Luisa
AU - Younkin, Linda
AU - Prada, Christian M.
AU - Yager, Debra
AU - Ohyagi, Yasumasa
AU - Eckman, Christopher B.
AU - Rosenberry, Terrone L.
AU - Younkin, Steven G.
PY - 1999/9/17
Y1 - 1999/9/17
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.274.38.26810
DO - 10.1074/jbc.274.38.26810
M3 - Article
C2 - 10480887
AN - SCOPUS:0033578719
SN - 0021-9258
VL - 274
SP - 26810
EP - 26814
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 38
ER -