Presenilin-1 uses phospholipase D1 as a negative regulator of β-amyloid formation

被引:88
作者
Cai, DM
Netzer, WJ
Zhong, MH
Lin, YX
Du, GW
Frohman, M
Foster, DA
Sisodia, SS
Xu, HX
Gorelick, FS
Greengard, P
机构
[1] Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA
[2] Rockefeller Univ, Fisher Ctr Res Alzheimer Dis, New York, NY 10021 USA
[3] CUNY Hunter Coll, Dept Biol Sci, New York, NY 10021 USA
[4] Ciphergen Biosyst Inc, Fremont, CA 94555 USA
[5] SUNY Stony Brook, Dept Pharmacol, Med Ctr, Stony Brook, NY 11794 USA
[6] SUNY Stony Brook, Ctr Dev Genet, Med Ctr, Stony Brook, NY 11794 USA
[7] Univ Chicago, Dept Neurobiol Pharmacol & Physiol, Chicago, IL 60637 USA
[8] Ctr Neurosci & Aging, Burnham Inst Med Res, La Jolla, CA 92037 USA
[9] Vet Affairs Connecticut Healthcare Syst, Dept Internal Med, West Haven, CT 06516 USA
[10] Yale Univ, West Haven, CT 06516 USA
关键词
beta-amyloid precursor protein; gamma-secretase complex activity; negative regulator; protein interaction; trans-Golgi network;
D O I
10.1073/pnas.0510708103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Presenilin (PS1/PS2) is a major component of gamma-secretase, the activity that mediates proteolysis of P-amyloid precursor protein to generate beta-amyloid (A beta). Here we demonstrate that PSI, through its loop region, binds to phospholipase D1 (PLD1), thereby recruiting it to the Golgi/trans-Golgi network. Overexpression of wildtype PLD1 reduces A beta generation. Conversely, down-regulation of endogenous PLD1 by small hairpin RNA elevates A beta production. The A beta-lowering effect of PLD1 is independent of its ability to promote vesicular budding of p-amyloid precursor protein. The data indicate that overexpression of PLD1 decreases, and downregulation of PLD1 increases, the catalytic activity, and the association of the subunits, of gamma-secretase.
引用
收藏
页码:1941 / 1946
页数:6
相关论文
共 36 条
[1]   Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins [J].
Annaert, WG ;
Esselens, C ;
Baert, V ;
Boeve, C ;
Snellings, G ;
Cupers, P ;
Craessaerts, K ;
De Strooper, B .
NEURON, 2001, 32 (04) :579-589
[2]   Lack of requirement for Presenilin1 in Notch1 signaling [J].
Berechid, BE ;
Thinakaran, G ;
Wong, PC ;
Sisodia, SS ;
Nye, JS .
CURRENT BIOLOGY, 1999, 9 (24) :1493-1496
[3]   Familial Alzheimer's disease-linked presenilin 1 variants elevate A beta 1-42/1-40 ratio in vitro and in vivo [J].
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 .
NEURON, 1996, 17 (05) :1005-1013
[4]   Phospholipase D1 corrects impaired βAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons [J].
Cai, DM ;
Zhong, MH ;
Wang, RS ;
Netzer, WJ ;
Shields, D ;
Zheng, H ;
Sisodia, SS ;
Foster, DA ;
Gorelick, FS ;
Xu, HX ;
Greengard, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (06) :1936-1940
[5]   Presenilin-1 regulates intracellular trafficking and cell surface delivery of β-amyloid precursor protein [J].
Cai, DM ;
Leem, JY ;
Greenfield, JP ;
Wang, P ;
Kim, BS ;
Wang, RS ;
Lopes, KO ;
Kim, SH ;
Zheng, H ;
Greengard, P ;
Sisodia, SS ;
Thinakaran, G ;
Xu, HX .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (05) :3446-3454
[6]  
CAPORASO GL, 1994, J NEUROSCI, V14, P3122
[7]  
DE SB, 1999, NATURE, V398, P518
[8]   Alzheimer's disease -: A firm base for drug development [J].
De Strooper, B ;
König, G .
NATURE, 1999, 402 (6761) :471-472
[9]   Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein [J].
De Strooper, B ;
Saftig, P ;
Craessaerts, K ;
Vanderstichele, H ;
Guhde, G ;
Annaert, W ;
Von Figura, K ;
Van Leuven, F .
NATURE, 1998, 391 (6665) :387-390
[10]   Phospholipase D2 localizes to the plasma membrane and regulates angiotensin II receptor endocytosis [J].
Du, GW ;
Huang, P ;
Liang, BT ;
Frohman, MA .
MOLECULAR BIOLOGY OF THE CELL, 2004, 15 (03) :1024-1030