Possible Role of Tau Protein Kinases in Pathogenesis of Alzheimer’s Disease

Imahori, Kazutomo; Hoshi, Masaharu; Ishiguro, Koichi; Sato, Kazuki; Takahashi, Miho; Shiurba, Robert; Yamaguchi, Hideyo; Takashima, Akihiko; Uchida, Tsuneko

doi:10.1016/s0197-4580(98)00025-6

Cited by 142 publications

(146 citation statements)

References 22 publications

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“…Among the several kinases involved in tau hyperphosphorylation (Singh et al, 1994;Johnson and Hartigan, 1999), CDK5 and GSK3␤ have been most implicated in the abnormal hyperphosphorylation of tau (Imahori and Uchida, 1997;Shelton and Johnson, 2004;Iqbal et al, 2005). Both kinases phosphorylate tau at a large number of sites, most of which are common to the two enzymes (Wang et al, 1998;Anderton et al, 2001).…”

Section: Atra Prevents App Processing and Phosphorylation Of Both Appmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

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Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to ␤-amyloid (A␤) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain A␤ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/ PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

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Section: Atra Prevents App Processing and Phosphorylation Of Both Appmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

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“…Glycogen synthase kinase 3 beta (GSK3␤) has been shown to phosphorylate tau in vitro, in cells and in neurons at sites that are phosphorylated in PHF. [4][5][6] Several groups 7,8 have shown that there is an increase in GSK3␤ levels in AD brain and that it is found to be associated with PHF. 7,9 GSK3␤ also binds to the presenilin 1 protein, 10 it is a critical intermediate in the wnt signalling pathway suggested to be altered in AD 11 and in the insulin signalling cascade, also possibly altered in AD.…”

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confidence: 99%

Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 β gene and promoter in late onset Alzheimer's disease

Russ¹,

Lovestone²,

Powell³

2001

Mol Psychiatry

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Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Glycogen synthase kinase 3 beta (GSK3␤) phosphorylates the microtubule associated protein tau at sites that are aberrantly phosphorylated in AD. GSK3␤ binds to presenilin 1 and plays a role in wnt and insulin signalling cascades, both of which have been proposed to be linked to AD. Moreover GSK3␤ activity may be altered in AD brain. These observations suggest a central role for GSK3␤ in AD and led us to investigate GSK3␤ as a candidate gene for AD. We sought to identify sequence variations in the gene and its promoter, as these could have an effect on activity and expression leading to abnormal function. Sequencing over 3000 bp of the GSK3␤ putative promoter revealed there to be five sequence variations, two of which were common (Ͼ10%). However on further examination none of these, either alone or in synergy, had any association with late onset AD. Stratification of the data by APOE ⑀4 status also produced no significant association. Sequencing of the GSK3␤ coding region revealed no variations. This would suggest that the aberrant phosphorylation of tau by GSK3␤ in AD is not due to sequence variations in the gene or its promoter. Molecular Psychiatry (2001) 6, 320-324.

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“…To conclusively demonstrate whether the poor kinetics was an artifact of tau expression, purification or handling or, in contrast, was a property intrinsic to tau itself, we engineered tau mutants in which the consensus sequences surrounding several established phosphorylation sites (40) were optimized for phosphorylation by CDK5. The corresponding wild-type and optimized consensus sequences are shown in Table 3.…”

Section: Resultsmentioning

confidence: 99%

No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro

Peterson¹,

Ando²,

Taketa³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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CDK5/p35 is a cyclin-dependent kinase essential for normal neuron function. Proteolysis of the p35 subunit in vivo results in CDK5/p25 that causes neurotoxicity associated with a number of neurodegenerative diseases. Whereas the mechanism by which conversion of p35 to p25 leads to toxicity is unknown, there is common belief that CDK5/p25 is catalytically hyperactive compared to CDK5/p35. Here, we have compared the steady-state kinetic parameters of CDK5/p35 and CDK5/p25 towards both histone H1, the best known substrate for both enzymes, and the microtubule-associated protein, tau, a physiological substrate whose in vivo phosphorylation is relevant to Alzheimer's disease. We show that the kinetics of both enzymes are the same towards either substrate in vitro. Furthermore, both enzymes display virtually identical kinetics towards individual phosphorylation sites in tau monitored by NMR. We conclude that conversion of p35 to p25 does not alter the catalytic efficiency of the CDK5 catalytic subunit by using histone H1 or tau as substrates, and that neurotoxicity associated with CDK5/p25 is unlikely attributable to CDK5 hyperactivation, as measured in vitro.Alzheimer's disease | neurotoxicity | NMR | protein kinase | proteolysis C DK5/p25 was first identified as a tau kinase (1, 2) that displayed a CDK1 (formerly p34 cdc2 ) -like substrate specificity in brain (3, 4). Of particular interest, phosphorylation of normal tau by CDK5/p25 could partially recapitulate several characteristics inherent to PHF-tau associated with Alzheimer's disease (1, 2). The CDK5 catalytic subunit was homologous to other CDKs and displayed ubiquitous expression (5), but p25 was originally discovered as a unique protein expressed predominantly in neurons, and generated by proteolytic cleavage of a larger protein precursor, p35 (6-9). Whereas CDK5/p35 is associated with normal neuron development and function (10), endogenous cleavage of p35 to p25 is associated with neuronal cell death, neuropathology, and is implicated in the progression of Alzheimer's disease (11-18), Parkinson's disease (19), and ALS (20). CDK5/p25, but not CDK5/p35, is toxic when overexpressed in transformed cell lines or when generated by cleavage of endogenous p35 in neurons (11,21,22). The cellular mechanism by which cleavage causes toxicity is not known, but in theory could relate to one or more known key differences between these two enzyme forms, including differences in subcellular distribution (11, 23), stability of the protein (11, 24), and/or cellular substrate specificity (11,25).There is common belief that the catalytic activity of CDK5/p25 is significantly elevated in comparison to CDK5/p35, and therefore that p25 causes "hyperactivity" of CDK5 compared to p35, contributing to its toxicity (10). To rigorously demonstrate its hyperactivity, however, it is necessary to show that the catalytic parameters associated with steady-state phosphorylation of substrates are different between the two enzymes. Hashiguchi et al. (26) previously conducted such experiments,...

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Possible Role of Tau Protein Kinases in Pathogenesis of Alzheimer’s Disease

Cited by 142 publications

References 22 publications

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 β gene and promoter in late onset Alzheimer's disease

No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro

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