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J Biol Chem, Vol. 274, Issue 38, 26810-26814, September 17, 1999

Glycosylphosphatidylinositol-anchored Proteins Play an Important Role in the Biogenesis of the Alzheimer's Amyloid beta -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, and Steven G. Younkin

From the Mayo Clinic, Jacksonville, Florida 32224

The Alzheimer's amyloid protein (Abeta ) is released from the larger amyloid beta -protein precursor (APP) by unidentified enzymes referred to as beta - and gamma -secretase. beta -Secretase cleaves APP on the amino side of Abeta producing a large secreted derivative (sAPPbeta ) and an Abeta -bearing C-terminal derivative that is subsequently cleaved by gamma -secretase to release Abeta . Alternative cleavage of the APP by alpha -secretase at Abeta 16/17 releases the secreted derivative sAPPalpha . In yeast, alpha -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 Abeta 40 and Abeta 42 in the medium but had no effect on sAPPalpha . A mutant CHO cell line (gpi85), which lacks GPI-anchored proteins, secreted lower levels of Abeta 40, Abeta 42, and sAPPbeta than its parental line (GPI+). When this parental line was treated with PI-PLC, Abeta 40, Abeta 42, and sAPPbeta 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 beta -secretase activity and Abeta secretion in mammalian cells. The cell-surface GPI-anchored protein(s) involved in Abeta biogenesis may be excellent therapeutic target(s) in Alzheimer's disease.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.


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