Cdk5 is a key factor in tau aggregation and tangle formation in vivo

被引:421
作者
Noble, W
Olm, V
Takata, K
Casey, E
O, M
Meyerson, J
Gaynor, K
LaFrancois, J
Wang, LL
Kondo, T
Davies, P
Burns, M
Veeranna
Nixon, R
Dickson, D
Matsuoka, Y
Ahlijanian, M
Lau, LF
Duff, K [1 ]
机构
[1] NYU, Nathan S Kline Inst Psychiat Res, Ctr Dementia Res, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA
[2] Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA
[3] Mayo Clin, Jacksonville, FL 32224 USA
[4] Pfizer Inc, Global Res & Dev, CNS Discovery, Groton, CT 06340 USA
关键词
D O I
10.1016/S0896-6273(03)00259-9
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Tau aggregation is a common feature of neurodegenerative diseases such as Alzheimer's disease, and hyperphosphorylation of tau has been implicated as a fundamental pathogenic mechanism in this process. To examine the impact of cdk5 in tau aggregation and tangle formation, we crossed transgenic mice overexpressing the cdk5 activator p25, with transgenic mice overexpressing mutant (P301L) human tau. Tau was hyperphosphorylated at several sites in the double transgenics, and there was a highly significant accumulation of aggregated tau in brainstem and cortex. This was accompanied by increased numbers of silver-stained neurofibrillary tangles (NFTs). Insoluble tau was also associated with active GSK. Thus, cdk5 can initiate a major impact on tau pathology progression that probably involves several kinases. Kinase inhibitors may thus be beneficial therapeutically.
引用
收藏
页码:555 / 565
页数:11
相关论文
共 50 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]   Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments [J].
Alonso, AD ;
Zaidi, T ;
Novak, M ;
Grundke-Iqbal, I ;
Iqbal, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (12) :6923-6928
[3]   A cdk5-p35 stable complex is involved in the β-amyloid-induced deregulation of cdk5 activity in hippocampal neurons [J].
Alvarez, A ;
Muñoz, JP ;
Maccioni, RB .
EXPERIMENTAL CELL RESEARCH, 2001, 264 (02) :266-274
[4]   Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease [J].
Augustinack, JC ;
Schneider, A ;
Mandelkow, EM ;
Hyman, BT .
ACTA NEUROPATHOLOGICA, 2002, 103 (01) :26-35
[5]  
Bancroft J.D., 1990, THEORY PRACTICE HIST, V3rd
[6]   ABNORMAL ALZHEIMER-LIKE PHOSPHORYLATION OF TAU-PROTEIN BY CYCLIN-DEPENDENT KINASES CDK2 AND CDK5 [J].
BAUMANN, K ;
MANDELKOW, EM ;
BIERNAT, J ;
PIWNICAWORMS, H ;
MANDELKOW, E .
FEBS LETTERS, 1993, 336 (03) :417-424
[7]   Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice [J].
Bian, F ;
Nath, R ;
Sobocinski, G ;
Booher, RN ;
Lipinski, WJ ;
Callahan, MJ ;
Pack, A ;
Wang, KKW ;
Walker, LC .
JOURNAL OF COMPARATIVE NEUROLOGY, 2002, 446 (03) :257-266
[8]   PHOSPHORYLATION OF SER(262) STRONGLY REDUCES BINDING OF TAU-PROTEIN TO MICROTUBULES - DISTINCTION BETWEEN PHF-LIKE IMMUNOREACTIVITY AND MICROTUBULE-BINDING [J].
BIERNAT, J ;
GUSTKE, N ;
DREWES, G ;
MANDELKOW, EM ;
MANDELKOW, E .
NEURON, 1993, 11 (01) :153-163
[9]   Regulated phosphorylation and dephosphorylation of tau protein: Effects on microtubule interaction, intracellular trafficking and neurodegeneration [J].
Billingsley, ML ;
Kincaid, RL .
BIOCHEMICAL JOURNAL, 1997, 323 :577-591
[10]   SILVER IMPREGNATION OF ALZHEIMER NEUROFIBRILLARY CHANGES COUNTERSTAINED FOR BASOPHILIC MATERIAL AND LIPOFUSCIN PIGMENT [J].
BRAAK, H ;
BRAAK, E ;
OHM, T ;
BOHL, J .
STAIN TECHNOLOGY, 1988, 63 (04) :197-200