Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3β transgenes

Brownlees, Janet; Irving, Nicholas G.; Brion, Jean-Pierre; Gibb, Barry; Wagner, Uta; Woodgett, James R.; Miller, Christopher C.J.

doi:10.1097/00001756-199710200-00013

Cited by 98 publications

(56 citation statements)

References 6 publications

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“…Also, overexpression of shaggy, the fly homologue of glycogen synthase kinase-3␤ (GSK-3␤) and a candidate kinase for tau phosphorylation, caused increased neurodegeneration, increased tau phosphorylation, and the appearance of filamentous tau aggregates (30). In contrast, in tau Tg mice, overexpression of GSK-3␤ alleviated transgeneinduced motor neuron defects and axonopathy (31), even though GSK-3␤ overexpression increases tau phosphorylation (31)(32)(33). Thus, the role of phosphorylation in tau-induced neurotoxicity is unclear.…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Kraemer

Zhang

Leverenz

et al. 2003

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

331

284

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Frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17) is caused by mutations in MAPT, the gene encoding tau. FTDP-17 begins with executive function deficits and other abnormal behaviors, which progress to dementia. Neurodegenerative changes include accumulation of aggregated tau as neuronal and glial fibrillary tangles. Aggregated tau is seen in numerous other neurodegenerative diseases, including Alzheimer's disease (AD). We expressed normal and FTDP-17 mutant human tau (mutations P 301 L and V 337 M ) in Caenorhabditis elegans to model tauopathy disorders. Tau pan-neuronal expression caused progressive uncoordinated locomotion (Unc), characteristic of nervous system defects in worms. Subsequently, insoluble tau accumulates and both soluble and insoluble tau is phosphorylated at many of the sites hyperphosphorylated in FTDP-17, AD, and other tauopathies. Substantial neurodegeneration, seen as bulges and gaps in nerve cords followed by loss of neurons, occurs after insoluble tau begins to accumulate. Axons show vacuoles, membranous infoldings, and whorls with associated amorphous tau accumulations and abnormal tau-positive aggregates. FTDP-17 mutation lines had a more severe Unc phenotype, accumulated more insoluble tau at a younger age, were more resistant to cholinergic inhibitors, and had more severe axonal degeneration when compared with lines expressing normal tau. The Unc phenotype is caused by a presynaptic defect. Postsynaptic transmission is intact. This transgenic model will enable mechanistic dissection of tau-induced neurodegeneration and identification of genes and compounds that inhibit pathological tau formation.A bnormally aggregated tau accumulates as neurofibrillary tangles and other lesions in many neurodegenerative diseases including Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17). For AD and most tauopathies, the role tau plays in disease initiation and progression is unknown. However, in FTDP-17, mutations in MAPT, the gene encoding tau, cause the disease (1-3), albeit by incompletely understood mechanisms. One hypothesis is that microtubule (MT)-mediated axonal transport is disrupted, an idea based on the reduced binding affinity of mutant tau for MTs (4). Another hypothesis is that aggregated tau is deleterious to cells, and in FTDP-17, aggregation is driven by either increased free tau concentrations (4) or mutationinduced acceleration of self-aggregation (5, 6). The critical toxic aggregate may be a dimer, a more extensive aggregate, tau filaments, or the end-stage tangles. The phosphorylation state of tau may also be important, as pathologic insoluble tau is hyperphosphorylated (7).To identify critical steps in tau-induced neurodegeneration, we generated a MAPT transgenic (Tg) Caenorhabditis elegans model of FTDP-17. Pan-neuronal expression of normal or FTDP-17 mutant MAPT resulted in altered behavior (uncoordinated movement), accumulation of insoluble phosphorylated tau, age-dependent loss of axons and neurons, and s...

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Section: Discussionmentioning

confidence: 99%

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Kraemer

Zhang

Leverenz

et al. 2003

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

331

284

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“…No differences in any of these epitopes between transgenic and wild-type mice were detected. 396͞404 (43), and in transgenic animals that overexpress GSK3␤ (44) or Mos kinase (45), increases in phosphorylated tau or neurofilament are observed. Chronic infusion of the phosphatase inhibitor okadaic acid also results in increased tau phosphorylation (46).…”

Section: Discussionmentioning

confidence: 99%

Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5

Ahlijanian

Barrezueta

Williams

et al. 2000

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

327

268

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Hyperphosphorylation of microtubule-associated proteins such as tau and neurofilament may underlie the cytoskeletal abnormalities and neuronal death seen in several neurodegenerative diseases including Alzheimer's disease. One potential mechanism of microtubule-associated protein hyperphosphorylation is augmented activity of protein kinases known to associate with microtubules, such as cdk5 or GSK3␤. Here we show that tau and neurofilament are hyperphosphorylated in transgenic mice that overexpress human p25, an activator of cdk5. The p25 transgenic mice display silver-positive neurons using the Bielschowsky stain. Disturbances in neuronal cytoskeletal organization are apparent at the ultrastructural level. These changes are localized predominantly to the amygdala, thalamus͞hypothalamus, and cortex. The p25 transgenic mice display increased spontaneous locomotor activity and differences from control in the elevated plus-maze test. The overexpression of an activator of cdk5 in transgenic mice results in increased cdk5 activity that is sufficient to produce hyperphosphorylation of tau and neurofilament as well as cytoskeletal disruptions reminiscent of Alzheimer's disease and other neurodegenerative diseases. Although many protein kinases phosphorylate tau at ADrelevant epitopes in vitro (reviewed in ref.2), only two have been copurified with microtubules, GSK3␤ and cdk5 (3, 4). To our knowledge, only these two kinases will phosphorylate tau in a cellular environment (e.g., refs. 5 and 6). We chose to focus on cdk5 because it is active predominantly in neurons whereas GSK3␤ plays a role in energy metabolism and is active in all cells. cdk5 is a member of the cyclin-dependent protein kinase gene family. Rather than cyclins, cdk5 associates with the positive allosteric regulators p35 (7), amino-terminal proteolytic fragments of p35 (e.g., p25; ref. 8), and p39 (9). These proteins share minimal amino acid sequence homology to cyclins, but the mechanism of activation of cdk5 by p25͞35 may be similar to the activation of cdk2 by cyclin A (10). p25͞35 is expressed predominantly in neurons, implying that most cdk5 activity is concentrated in neuronal structures (7,8). cdk5 plays a pivotal role in neuronal development as evidenced by the abnormal corticogenesis and perinatal lethality of cdk5 knockout mice (11) and the disturbances in neuronal migration and early death in p35 knockout mice (12). A number of potential cdk5 substrates have been identified and most are consistent with a putative role in neurite outgrowth and plasma membrane dynamics. These include cytoskeletal proteins such as tau and neurofilament (e.g., refs. 13 and 14) and synaptic vesicle proteins (15, 16). To clarify the potential role of cdk5 in neurodegenerative diseases in vivo, we overexpressed human p25 in the brains of transgenic mice to determine whether increased cdk5 activity would lead to hyperphosphorylation of tau and neurofilament and͞or cytoskeletal disturbances. Materials and MethodsAnimal Handling. All experimentation was performed under...

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“…L'augmentation de l'activité de la GSK-3 dans les cerveaux de patients atteints de MA coïncide au niveau spatiotemporel avec les DNF [2]. La GSK-3 surexprimée dans le cerveau de souris transgéniques provoque l'hyperphosphorylation de la protéine Tau, le désassemblage des microtubules et l'apparition de DNF [3,4]. > Le vieillissement de la population entraîne une augmentation spectaculaire de l'incidence des maladies neurodégénératives dans les pays industrialisés.…”

Section: Dégénérescences Neurofibrillairesunclassified

“…« Ces agrégats -appelés aussi corps de Lewy -exprimant la synucléine et l'ubiquitine dans le corps cellulaire ou les neurites de certains neurones dopaminergiques constituent les stigmates neuropathologiques caractéristiques du processus neurodégénératif de la MP » (tiré de [44]). 3 « L' -synucléine est une protéine neuronale de 140 acides aminés, extrêmement conservée chez les vertébrés. Elle est enrichie dans de nombreuses régions céré-brales (néocortex, hippocampe, gyrus denté, bulbe olfactif, striatum, thalamus, cervelet) dans lesquelles elle se concentre au niveau des terminaisons synaptiques.…”

Section: Gsk-3b Et Maladie De Parkinsonunclassified

GSK-3β : une kinase au cœur des maladies neuro-dégénératives ?

Petit-Paitel

2010

Med Sci (Paris)

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Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3β transgenes

Cited by 98 publications

References 6 publications

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy

Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5

GSK-3β : une kinase au cœur des maladies neuro-dégénératives ?

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