Age-Dependent Emergence and Progression of a Tauopathy in Transgenic Mice Overexpressing the Shortest Human Tau Isoform

Ishihara, Takeshi; Hong, Ming; Zhang, Bin; Nakagawa, Yasushi; Lee, Michael K.; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1016/s0896-6273(00)81127-7

Cited by 544 publications

(449 citation statements)

References 45 publications

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“…Treatment with paclitaxel restores fast axonal transport in spinal axons, increases axonal MTs, and ameliorates motor impairments in tau transgenic mice that developed filamentous tau inclusions (mostly in the spinal cord) (Ishihara et al 1999(Ishihara et al , 2001Zhang et al 2005). Paclitaxel also blocks Aβ-induced phosphorylation of tau by preventing the cleavage of p35 by calpain (Li et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

2008

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Neurofibrillary tangles are one of the pathologic hallmarks of Alzheimer's disease (AD). They are composed of paired helical filaments (PHF) containing hyperphosphorylated forms of tau. Hyperphosphorylation of certain tau sites favors its dissociation from the microtubules (MT), interfering with axonal transport and compromising the function and viability of neurons. Reappearance of cell cycle proteins have been reported in neurons exhibiting tau aggregation, suggesting that an aberrant cell cycle occurs before neurons die. Cell cycle suppression in neurons is crucial to survival, thus prevention of progression through the cell cycle may offer a therapeutic approach. Using a neuroblastoma cell line overexpressing 3-repeat (3R) tau, we investigated the effects of cell cycle inhibitors on tau phosphorylation. G2/M phase inhibitors did not alter phosphorylation of tau at Ser-202 and Ser-396/404 at the lower doses, but did at higher doses. Ser-202 and Ser-396/404 are phosphorylation sites of early and late neurofibrillary tangles, respectively, in AD. Cisplatin, a G1 phase inhibitor, did not phosphorylate tau. Cyclophosphamide and phosphoramide mustard, DNA cross-linking agents, decreased tau phosphorylation at Ser-396/404 site, but increased phosphorylation at Ser-202. These studies demonstrate that the G2/M blockers have a dose-dependent effect on tau phosphorylation. This seems to be a consequence of both the disruption of MT-organization and MT-dynamics when doses are higher, but only a disruption of MT-dynamics with lower doses. These results are also in agreement with the lack of phosphorylation seen for cisplatin, another inhibitor that produces disruption of the MT-dynamics.

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Section: Discussionmentioning

confidence: 99%

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

2008

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“…40 -45 They have tau immunoreactivity in neurons and their processes, but only one study has demonstrated immunolabeling of astrocyte-like cells at the light microscopic level. 42 Another study 43 showed aggregates of 10-to 20-nm straight filaments in myelinated spinal cord axons. The filaments were immunolabeled by antibodies to tau, tubulin, and neurofilaments.…”

Section: Discussionmentioning

confidence: 99%

Filamentous Tau in Oligodendrocytes and Astrocytes of Transgenic Mice Expressing the Human Tau Isoform with the P301L Mutation

Lin

Lewis

Yen

et al. 2003

The American Journal of Pathology

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We recently reported a transgenic mouse line (JNPL3) that expresses mutant (P301L) tau and develops neurofibrillary tangles composed of filamentous tau aggregates. Here we show that these mice have abnormal tau filaments not only in neurons, but also in oligodendrocytes and astrocytes. Similar results were detected in another transgenic line (JNPL2؉3؉) that expresses the longest human tau isoform with the P301L mutation. The ultrastructure of the tau filaments and immunoreactivity with tau and ubiquitin antibodies were similar in glia and neurons. Given similarities of the lesions in the mice to human neuronal and glial inclusions, these transgenic mice appear to be a valuable model to study pathogenesis of the neurodegenerative tauopathies.

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“…In tissue culture, phosphorylation of tau repeats resulted in transport impairment, and deficits in fast anterograde transport were described in tau transgenic mice. 27,220 One major advantage of microtubule-stabilizing strategies is the availability of approved and well-established chemotherapeutic drugs such as taxol. Taxol and its derivative taxane analog TX67 stabilize microtubules and promote tubulin polymerization.…”

Section: Microtubule-stabilizing Drugsmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Age-Dependent Emergence and Progression of a Tauopathy in Transgenic Mice Overexpressing the Shortest Human Tau Isoform

Cited by 544 publications

References 45 publications

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

Filamentous Tau in Oligodendrocytes and Astrocytes of Transgenic Mice Expressing the Human Tau Isoform with the P301L Mutation

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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