A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains

被引:151
作者
Tseng, HC
Zhou, Y
Shen, Y
Tsai, LH [1 ]
机构
[1] Harvard Univ, Sch Med, Dept Pathol, Howard Hughes Med Inst, Boston, MA 02115 USA
[2] Sun Hlth Res Inst, Haledman Lab Mol & Cellular Neurobiol, Sun City, AZ 85351 USA
基金
美国国家卫生研究院;
关键词
cyclin-dependent kinase 5; cyclin-dependent kinase 5 activator; proteolysis; Alzheimer's disease;
D O I
10.1016/S0014-5793(02)02934-4
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
P25, a calpain cleavage product of the cyclin-dependent kinase 5 (Cdk5) activator p35, causes prolonged activation of Cdk5. Although p25 has been shown to accumulate in brains of patients with Alzheimer's disease (AD), it is not known whether p25 accumulation in AD is brain region-specific. We analyzed the amounts of p25 and p35 in human autopsy samples from multiple brain regions including frontal cortex, inferior parietal cortex and hippocampus using immunoblotting assays. Our results show that the p25-p35 indices are higher in AD than in the control groups in all three brain regions. The most significant difference in p25-p35 indices between AD and control groups is in the frontal cortex. No significant difference in calpain activity between AD and control groups is observed, indicating that postmortem calpain activation cannot account for the elevation of p25/p35 ratios in AD brains. Our results support the notion that p25 accumulation deregulates Cdk5 activity in AD brains, and the deregulated Cdk5 activity may contribute to the pathogenesis of AD. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
引用
收藏
页码:58 / 62
页数:5
相关论文
共 19 条
[1]   Hyperphosphorylated tan and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5 [J].
Ahlijanian, MK ;
Barrezueta, NX ;
Williams, RD ;
Jakowski, A ;
Kowsz, KP ;
McCarthy, S ;
Coskran, T ;
Carlo, A ;
Seymour, PA ;
Burkhardt, JE ;
Nelson, RB ;
McNeish, JD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (06) :2910-2915
[2]   Inhibition of tau phosphorylating protein kinase cdk5 prevents β-amyloid-induced neuronal death [J].
Alvarez, A ;
Toro, R ;
Cáceres, A ;
Maccioni, RB .
FEBS LETTERS, 1999, 459 (03) :421-426
[3]  
[Anonymous], 1983, Statistical methods
[4]   Quantitative assessment of pituitary resistance to thyroid hormone from plots of the logarithm of thyrotropin versus serum free thyroxine index [J].
Ercan-Fang, S ;
Schwartz, HL ;
Mariash, CN ;
Oppenheimer, JH .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2000, 85 (06) :2299-+
[5]   PERIKARYAL ACCUMULATION AND PROTEOLYSIS OF NEUROFILAMENT PROTEINS IN THE POSTMORTEM RAT-BRAIN [J].
GEDDES, JW ;
BONDADA, V ;
TEKIRIAN, TL ;
PANG, Z ;
SIMAN, RG .
NEUROBIOLOGY OF AGING, 1995, 16 (04) :651-660
[6]   Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25 [J].
Kusakawa, G ;
Saito, T ;
Onuki, R ;
Ishiguro, K ;
Kishimoto, T ;
Hisanaga, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (22) :17166-17172
[7]   Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain [J].
Lee, KY ;
Clark, AW ;
Rosales, JL ;
Chapman, K ;
Fung, T ;
Johnston, RN .
NEUROSCIENCE RESEARCH, 1999, 34 (01) :21-29
[8]   Neurotoxicity induces cleavage of p35 to p25 by calpain [J].
Lee, MS ;
Kwon, YT ;
Li, MW ;
Peng, JM ;
Friedlander, RM ;
Tsai, LH .
NATURE, 2000, 405 (6784) :360-364
[9]   NEURONAL CDC2-LIKE KINASE [J].
LEW, J ;
WANG, JH .
TRENDS IN BIOCHEMICAL SCIENCES, 1995, 20 (01) :33-37
[10]   Ischemic cell death in brain neurons [J].
Lipton, P .
PHYSIOLOGICAL REVIEWS, 1999, 79 (04) :1431-1568