Tau protein isoforms, phosphorylation and role in neurodegenerative disorders11These authors contributed equally to this work.

Buée, Luc; Bussière, Thierry; Buée‐Scherrer, Valérie; Delacourte, André; Hof, Patrick R.

doi:10.1016/s0165-0173(00)00019-9

Cited by 1,757 publications

(1,531 citation statements)

References 390 publications

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“…Reflecting astrocytic metabolism, the percentage enrichment of [4,[5][6][7][8][9][10][11][12][13] C]glutamate, [4,[5][6][7][8][9][10][11][12][13] C]glutamine and [1,2-13 C]GABA were significantly increased in the cerebral cortex of pR5 mice compared with controls ( Figure 2B). Calculation of M þ 2 isotopomers from NMRS results demonstrated that the percentage enrichment of M þ 2 glutamate and glutamine were increased, whereas that of M þ 2 GABA remained unaltered (Table 3).…”

Section: Concentrations Of Metabolitesmentioning

confidence: 99%

“…The transfer of metabolites between neurons and astrocytes in cortex appeared to remain normal. This was indicated by the increase in percentage enrichment of both [4-13 C] glutamate and glutamine (which can suggest normal transfer of glutamate from neurons to astrocytes) and in that of [4,[5][6][7][8][9][10][11][12][13] …”

Section: Decreased Glutamate Level In Hippocampusmentioning

confidence: 99%

“…4,5 Tau is subsequently translocated to the somatodendritic compartment where it, with time, accumulates into filamentous aggregates and assembles into neurofibrillary tangles (NFTs). 4,6 The discovery of a range of mutations in the tau gene (microtubule-associated protein tau; MAPT) in FTDP-17 in humans has firmly established that tau dysfunction can lead to neurodegeneration and dementia, [7][8][9][10] although mutations in the tau gene have not been identified in AD.…”

Section: Introductionmentioning

confidence: 99%

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Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Nilsen

Rae

Ittner

et al. 2013

J Cereb Blood Flow Metab

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In neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia, the protein tau is hyperphosphorylated and eventually aggregates to develop neurofibrillary tangles. Here, the consequences of tau hyperphosphorylation on both neuronal and astrocytic metabolism and amino-acid neurotransmitter homeostasis were assessed in transgenic mice expressing the pathogenic mutation P301L in the human tau gene (pR5 mice) compared with nontransgenic littermate controls. Mice were injected with the neuronal and astrocytic substrate [1-13 C]glucose and the astrocytic substrate [1,2-13 C]acetate. Hippocampus and cerebral cortex extracts were analyzed using 1 H and 13 C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry and high-performance liquid chromatography. The glutamate level was reduced in the hippocampus of pR5 mice, accompanied by reduced incorporation of 13 C label derived from [1-13 C]glucose in glutamate. In the cerebral cortex, glucose utilization as well as turnover of glutamate, glutamine, and GABA, were increased. This was accompanied by a relative increase in production of glutamate via the pyruvate carboxylation pathway in cortex. Overall, we revealed that astrocytes as well as glutamatergic and GABAergic neurons in the cortex of pR5 mice were in a hypermetabolic state, whereas in the hippocampus, where expression levels of mutant human tau are the highest, glutamate homeostasis was impaired.

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Section: Concentrations Of Metabolitesmentioning

confidence: 99%

Section: Decreased Glutamate Level In Hippocampusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Nilsen

Rae

Ittner

et al. 2013

J Cereb Blood Flow Metab

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“…22,23 At 48 h post-transfection, we checked the phosphorylation level of t, at its Ser 202 and Thr 205 residues by Western blotting in APLP2 ICDs-transfected PC12 cells and in rat primary neurons using AT8 antibody. In APLP2 ICDs-transfected cells, the level of t phosphorylation at Ser 202 and Thr 205 residues was found to be significantly increased without changes in nonphosphorylated form of t. However, no significant increase in t phosphorylation was found for Y738G mutated APLP2 ICDs-transfected groups (Figure 3e).…”

Section: Figure 3 (Continued)mentioning

confidence: 99%

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

et al. 2006

Cell Death Differ

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Amyloid precursor protein (APP) is a member of a gene family that includes two APP-like proteins, APLP1 and 2. Recently, it has been reported that APLP1 and 2 undergo presenilin-dependent c-secretase cleavage, as does APP, resulting in the release of an B6 kDa intracellular C-terminal domain (ICD), which can translocate into the nucleus. In this study, we demonstrate that the APLP2-ICDs interact with CP2/LSF/LBP1 (CP2) transcription factor in the nucleus and induce the expression of glycogen synthase kinase 3b (GSK-3b), which has broad-ranged substrates such as s-and b-catenin. The significance of this finding is substantiated by the in vivo evidence of the increase in the immunoreactivities for the nuclear C-terminal fragments of APLP2, and for GSK-3b in the AD patients' brain. Taken together, these results suggest that APLP2-ICDs contribute to the AD pathogenesis, by inducing GSK-3b expression through the interaction with CP2 transcription factor in the nucleus. The pathology of Alzheimer's disease (AD) is characterized by the deposition of neuritic plaques, of which the principal components are 40 and 42 amino-acid amyloid beta peptides (Ab) derived from amyloid precursor protein (APP). 1 APP belongs to a family of conserved type I transmembrane proteins including Apl-1 in Caenorhabditis elegans, 2 Appl in Drosophila, 3 and APP, 4 APP-like protein 1 (APLP1) 5 and APLP2 6,7 in mammals.APLP1 and 2 display substantial amino-acid and domain homologies with APP. Although they do not have an Ab domain, their intracellular C-terminal domains (ICDs) are highly similar to that of APP. 8 APLP1 is known to be implicated in synaptogenesis, 9,10 and recombinant APLP2 possesses an ability to promote neurite outgrowth. 11 However, their physiological roles in neurons are still not fully understood. In the brains of AD patients, APLP2 immunoreactivity has been detected in a subset of neuritic plaques, 12 suggesting that APLP2 might be involved in the pathogenesis of AD.APLP2 matures through the same secretory/cleavage pathway as APP 7 and previously, APLP1 and 2 were reported to be processed by g-secretase in a presenilin 1-dependent manner. 8,10 The APLP family can be also cleaved by esecretase to generate the ICD composed of the last 50 amino acids of APLPs C-terminus (C50). 13,14 Moreover, the ICDs of APLP1 and APLP2 produced by g-secretase enhanced Fe65-dependent gene transcriptional activation, as have been reported for the APP intracellular domain (AICD). 10 Fe65, which is known to be ones of the adaptor proteins for APP, contains three protein-protein interaction domains, a WW and two phosphotyrosine binding (PTB) domains. The PTB2 domain, which is located in the C-terminal half of the molecule, is responsible for the interaction between Fe65 and the cytosolic tail of APP through the YENPTY domain of APP. 15 Here, we demonstrate that the ICDs of APLP2 (APLP2-ICDs: C57, C50) interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase 3b (GSK-3b) expression, whereas their point mutants with...

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“…This dynamic behaviour, called dynamic instability, guarantees cellular homeostasis and is tightly regulated by stabilizing and destabilizing MT associated proteins (MAPs). Over the past several decades, significant advancements have been made in our understanding of the mechanism of action of stabilizing MAPs, such as Tau [1][2][3][4]. More recently, however, attention has turned to a family of destabilizing molecules: stathmin and its family members that share the same SLD (stathmin like domain), such as RB3 [5].…”

Section: Introductionmentioning

confidence: 99%

Stathmin/Op18 is a novel mediator of vinblastine activity

et al. 2008

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Microtubule (MT) dynamic instability is tightly regulated by stabilizing and destabilizing proteins, the latter being exemplified by stathmin/Op18, a protein known to destabilize MTs. Studies in cells have indicated that the level of stathmin expression modifies the cytotoxicity of antimicrotubule drugs, such as vinblastine (VLB). Using isothermal titration calorimetry and analytical ultracentrifugation, we show that VLB increases the affinity of stathmin for tubulin 50-fold (and vice versa). These results are the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and reveal a new mechanism of action for VLB. Structured summary:MINT-6603918: tubulin beta (uniprotkb:Q9H4B7), tubulin alpha (uniprotkb:Q71U36) and stathmin (uniprotkb:Q71U36) physically interact (MI:0218) by cosedimentation (MI:0027) MINT-6603930: tubulin alpha (uniprotkb:Q71U36) physically interacts (MI:0218) with tubulin beta (uniprotkb:Q9H4B7) and stathmin (uniprotkb:P16949) by isothermal titration calorimetry (MI:0065)

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Tau protein isoforms, phosphorylation and role in neurodegenerative disorders11These authors contributed equally to this work.

Cited by 1,757 publications

References 390 publications

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

Stathmin/Op18 is a novel mediator of vinblastine activity

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