Divergent roles of GSK3 and CDK5 in APP processing

被引：114

作者：

Ryder, J ^{[1
]}

Su, YA

Liu, F

Li, BL

Zhou, Y

Ni, BH

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA

[2] Indiana Univ, Sch Med, Dept Psychiat & Anat, Indianapolis, IN 46202 USA

[3] Indiana Univ, Sch Med, Dept Cell Biol, Indianapolis, IN 46202 USA

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2003年 / 312卷 / 04期

关键词：

Alzheimer's disease; APP; A beta; CDK5; GSK3; antisense;

D O I：

10.1016/j.bbrc.2003.11.014

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：

Glycogen synthase kinase-3 (GSK3) and cyclin-dependent kinase 5 (CDK5) are related serine/threonine kinases that have been well studied for their role in tau hyperphosphorylation, however, little is known about their significance in APP processing. Here we report that GSK3 and CDK5 are involved in APP processing in a divergent manner. Specific inhibition of cellular GSK3 by lithium or GSK3beta antisense elicits a reduction in Abeta. Conversely, negative modulation of cellular CDK5 activity by CDK5 inhibitor, roscovitine, or CDK5 antisense stimulates Abeta production. Neither GSK3 nor CDK5 inhibition by these means significantly affected cellular APP levels or APP maturation. Moreover, oral administration of lithium significantly reduces Abeta production whereas direct ICV administration of roscovitine augmented Abeta production in the brains of PDAPP (APP(V717F)) mice. Our data support a function for both GSK3 and CDK5 in APP processing, further implicating these two kinases in the pathogenesis of Alzheimer's disease. (C) 2003 Elsevier Inc. All rights. reserved.

引用

页码：922 / 929

页数：8

共 34 条

[1]

Anderton BH, 2001, BIOCHEM SOC SYMP, V67, P73

[2]

Aplin AE, 1996, J NEUROCHEM, V67, P699

[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] Increased amyloid-beta 42(43) in brains of mice expressing mutant presenilin 1 [J].

Duff, K ;

Eckman, C ;

Zehr, C ;

Yu, X ;

Prada, CM ;

Pereztur, J ;

Hutton, M ;

Buee, L ;

Harigaya, Y ;

Yager, D ;

Morgan, D ;

Gordon, MN ;

Holcomb, L ;

Refolo, L ;

Zenk, B ;

Hardy, J ;

Younkin, S .

NATURE, 1996, 383 (6602) :710-713

[5] GLYCOGEN-SYNTHASE KINASE-3 FROM RABBIT SKELETAL-MUSCLE - SEPARATION FROM CYCLIC-AMP-DEPENDENT PROTEIN-KINASE AND PHOSPHORYLASE-KINASE [J].

EMBI, N ;

RYLATT, DB ;

COHEN, P .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 1980, 107 (02) :519-527

[6]

Flaherty DB, 2000, J NEUROSCI RES, V62, P463, DOI 10.1002/1097-4547(20001101)62:3<463::AID-JNR16>3.0.CO

[7]

2-7

[8] GSK3 takes centre stage more than 20 years after its discovery [J].

Frame, S ;

Cohen, P .

BIOCHEMICAL JOURNAL, 2001, 359 (01) :1-16

[9] ALZHEIMER-TYPE NEUROPATHOLOGY IN TRANSGENIC MICE OVEREXPRESSING V717F BETA-AMYLOID PRECURSOR PROTEIN [J].

GAMES, D ;

ADAMS, D ;

ALESSANDRINI, R ;

BARBOUR, R ;

BERTHELETTE, P ;

BLACKWELL, C ;

CARR, T ;

CLEMENS, J ;

DONALDSON, T ;

GILLESPIE, F ;

GUIDO, T ;

HAGOPIAN, S ;

JOHNSONWOOD, K ;

KHAN, K ;

LEE, M ;

LEIBOWITZ, P ;

LIEBERBURG, I ;

LITTLE, S ;

MASLIAH, E ;

MCCONLOGUE, L ;

MONTOYAZAVALA, M ;

MUCKE, L ;

PAGANINI, L ;

PENNIMAN, E ;

POWER, M ;

SCHENK, D ;

SEUBERT, P ;

SNYDER, B ;

SORIANO, F ;

TAN, H ;

VITALE, J ;

WADSWORTH, S ;

WOLOZIN, B ;

ZHAO, J .

NATURE, 1995, 373 (6514) :523-527

[10] Cyclin-dependent protein kinase 5 (Cdk5) and the regulation of neurofilament metabolism [J].

Grant, P ;

Sharma, P ;

Pant, HC .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (06) :1534-1546

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