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

被引:49
作者
Sambamurti, K [1 ]
Sevlever, D [1 ]
Koothan, T [1 ]
Refolo, LM [1 ]
Pinnix, I [1 ]
Gandhi, S [1 ]
Onstead, L [1 ]
Younkin, L [1 ]
Prada, CM [1 ]
Yager, D [1 ]
Ohyagi, Y [1 ]
Eckman, CB [1 ]
Rosenberry, TL [1 ]
Younkin, SG [1 ]
机构
[1] Mayo Clin, Jacksonville, FL 32224 USA
关键词
D O I
10.1074/jbc.274.38.26810
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Alzheimer's amyloid protein (A beta) is released hom 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 A beta producing a large secreted derivative (sAPP beta) and an A beta-bearing C-terminal derivative that is subsequently cleaved by gamma-secretase to release A beta. Alternative cleavage of the APP by alpha-secretase at A beta 16/17 releases the secreted derivative sAPP alpha. 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 A beta 40 and A beta 42 in the medium but had no effect on sAPP alpha, A mutant CHO cell line (gpi85), which lacks GPI-anchored proteins, secreted lower levels of A beta 40, A beta 42,and sAPP beta than its parental line (GPI+), When this parental line was treated with PI-PLC, A beta 40, A beta 42, and sAPP beta 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 A beta secretion in mammalian cells, The cell-surface GPI-anchored protein(s) involved in A beta biogenesis may be excellent therapeutic target(s) in Alzheimer's disease.
引用
收藏
页码:26810 / 26814
页数:5
相关论文
共 43 条
  • [1] SECRETED PLACENTAL ALKALINE-PHOSPHATASE - A POWERFUL NEW QUANTITATIVE INDICATOR OF GENE-EXPRESSION IN EUKARYOTIC CELLS
    BERGER, J
    HAUBER, J
    HAUBER, R
    GEIGER, R
    CULLEN, BR
    [J]. GENE, 1988, 66 (01) : 1 - 10
  • [2] A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells
    Black, RA
    Rauch, CT
    Kozlosky, CJ
    Peschon, JJ
    Slack, JL
    Wolfson, MF
    Castner, BJ
    Stocking, KL
    Reddy, P
    Srinivasan, S
    Nelson, N
    Boiani, N
    Schooley, KA
    Gerhart, M
    Davis, R
    Fitzner, JN
    Johnson, RS
    Paxton, RJ
    March, CJ
    Cerretti, DP
    [J]. NATURE, 1997, 385 (6618) : 729 - 733
  • [3] Familial Alzheimer's disease-linked presenilin 1 variants elevate A beta 1-42/1-40 ratio in vitro and in vivo
    Borchelt, DR
    Thinakaran, G
    Eckman, CB
    Lee, MK
    Davenport, F
    Ratovitsky, T
    Prada, CM
    Kim, G
    Seekins, S
    Yager, D
    Slunt, HH
    Wang, R
    Seeger, M
    Levey, AI
    Gandy, SE
    Copeland, NG
    Jenkins, NA
    Price, DL
    Younkin, SG
    [J]. NEURON, 1996, 17 (05) : 1005 - 1013
  • [4] Axonal amyloid precursor protein expressed by neurons in vitro is present in a membrane fraction with caveolae-like properties
    Bouillot, C
    Prochiantz, A
    Rougon, G
    Allinquant, B
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (13) : 7640 - 7644
  • [5] Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor
    Buxbaum, JD
    Liu, KN
    Luo, YX
    Slack, JL
    Stocking, KL
    Peschon, JJ
    Johnson, RS
    Castner, BJ
    Cerretti, DP
    Black, RA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (43) : 27765 - 27767
  • [6] PROCESSING OF ALZHEIMER BETA-A4 AMYLOID PRECURSOR PROTEIN - MODULATION BY AGENTS THAT REGULATE PROTEIN-PHOSPHORYLATION
    BUXBAUM, JD
    GANDY, SE
    CICCHETTI, P
    EHRLICH, ME
    CZERNIK, AJ
    FRACASSO, RP
    RAMABHADRAN, TV
    UNTERBECK, AJ
    GREENGARD, P
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (15) : 6003 - 6006
  • [7] RELEASE OF EXCESS AMYLOID BETA-PROTEIN FROM A MUTANT AMYLOID BETA-PROTEIN PRECURSOR
    CAI, XD
    GOLDE, TE
    YOUNKIN, SG
    [J]. SCIENCE, 1993, 259 (5094) : 514 - 516
  • [8] CHECLER F, 1995, J NEUROCHEM, V65, P1431
  • [9] MUTATION OF THE BETA-AMYLOID PRECURSOR PROTEIN IN FAMILIAL ALZHEIMERS-DISEASE INCREASES BETA-PROTEIN PRODUCTION
    CITRON, M
    OLTERSDORF, T
    HAASS, C
    MCCONLOGUE, L
    HUNG, AY
    SEUBERT, P
    VIGOPELFREY, C
    LIEBERBURG, I
    SELKOE, DJ
    [J]. NATURE, 1992, 360 (6405) : 672 - 674
  • [10] Detection and quantitation of cellularly derived amyloid β peptides by immunoprecipitation-HPLC-MS
    Clarke, NJ
    Tomlinson, AJ
    Ohyagi, Y
    Younkin, S
    Naylor, S
    [J]. FEBS LETTERS, 1998, 430 (03) : 419 - 423