Structure of tau protein and assembly into paired helical filaments

Friedhoff, Peter; Bergen, Martin von; Mandelkow, Eva‐Maria

doi:10.1016/s0925-4439(00)00038-7

Cited by 144 publications

(107 citation statements)

References 113 publications

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“…Conditions-Neuronal cells normally have a reducing environment maintained by an excess of glutathione (1,5,37). To mimic the reducing environment present in normal neuronal cells and block the formation of an intramolecular disulfide bond, DTT, a strong reducing agent, was used in this study.…”

Section: Effect Of Zn 2ϩ On Tau Aggregation Under Reducing or Oxidativementioning

confidence: 99%

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Low Micromolar Zinc Accelerates the Fibrillization of Human Tau via Bridging of Cys-291 and Cys-322

Zhu

et al. 2009

Journal of Biological Chemistry

171

172

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Section: Effect Of Zn 2ϩ On Tau Aggregation Under Reducing or Oxidativementioning

confidence: 99%

“…They are located in repeats 2 and 3 of the four-repeat microtubule binding domain (37,39). Little is known about the role of such cysteine residues in Tau assembly, because their substitution with other amino acids has no effect on Tau filament morphology (40).…”

Section: Cys-291 and Cys-322 Are Key Residues In The Interaction Of Znmentioning

confidence: 99%

Low Micromolar Zinc Accelerates the Fibrillization of Human Tau via Bridging of Cys-291 and Cys-322

Zhu

et al. 2009

Journal of Biological Chemistry

171

172

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“…The tau protein binds microtubules, polymerizes actin, and participates in intracellular trafficking. 119,120 In healthy adult brain, tau is located in axons, but in AD and other tauopathies, it is hyperphosphorylated and is found in cell bodies and dendrites as well as axons. Pathogenic mutations in the tau gene that cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) either reduce the ability of tau to bind to microtubules or alter the splicing of exon 10 resulting in increased 4 repeat tau isoforms (containing 4 microtubule-binding domains).…”

Section: Tau Transgenic Mouse Modelsmentioning

confidence: 99%

Transgenic models of Alzheimer’s disease: Learning from animals

2005

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Summary:As the scope of the problem of Alzheimer's disease (AD) grows due to an aging population, research into the devastating condition has taken on added urgency. Rare inherited forms of AD provide insight into the molecular pathways leading to degeneration and have made possible the development of transgenic animal models. Several of these models are based on the overexpression of amyloid precursor protein (APP), presenilins, or tau to cause production and accumulation of amyloid-␤ into plaques or hyperphosphorylated tau into neurofibrillary tangles. Producing these characteristic neuropathological lesions in animals causes progressive neurodegeneration and in some cases similar behavioral disruptions to those seen in AD patients. Knockout models of proteins involved in AD have also been generated to explore the native functions of these genes and examine whether pathogenesis is due to loss of function or toxic gain of function in these systems. Although none of the transgenic lines models the human condition exactly, the ability to study similar pathological processes in living animals have provided numerous insights into disease mechanisms and opportunities to test therapeutic agents. This chapter reviews animal models of AD and their contributions to developing therapeutic approaches for AD.

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“…phosphorylation ͉ neurofibrillary tangles ͉ Alzheimer's disease ͉ tau protein N eurofibrillary tangles (NFTs) primarily comprise aggregated, microtubule-associated protein tau (1). Tau in NFTs aggregates in the neuronal cell body, it is hyperphosphorylated at specific sites (2), and it takes on an abnormal conformation (ref.…”

mentioning

confidence: 99%

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degenerationin vivo

Noble

Planel

Zehr

et al. 2005

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

642

471

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Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.phosphorylation ͉ neurofibrillary tangles ͉ Alzheimer's disease ͉ tau protein

show abstract

Structure of tau protein and assembly into paired helical filaments

Cited by 144 publications

References 113 publications

Low Micromolar Zinc Accelerates the Fibrillization of Human Tau via Bridging of Cys-291 and Cys-322

Low Micromolar Zinc Accelerates the Fibrillization of Human Tau via Bridging of Cys-291 and Cys-322

Transgenic models of Alzheimer’s disease: Learning from animals

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degenerationin vivo

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