Abnormal tau phosphorylation at Ser396 in alzheimer's disease recapitulates development and contributes to reduced microtubule binding

@article{Bramblett1993AbnormalTP,
  title={Abnormal tau phosphorylation at Ser396 in alzheimer's disease recapitulates development and contributes to reduced microtubule binding},
  author={Gregory T. Bramblett and Michel Goedert and Ross Jakes and Sandra E. Merrick and John Q. Trojanowski and Virginia M. -Y. Lee},
  journal={Neuron},
  year={1993},
  volume={10},
  pages={1089-1099}
}

Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38δ at Thr50 promotes microtubule assembly

A role for Tau in the adaptative response of neurons to stress is suggested and it is indicated that SAPK4/p38δ and/or SAPK3/p 38δ may contribute to the hyperphosphorylation of Tau inThe human tauopathies.

Casein Kinase 1 Delta Phosphorylates Tau and Disrupts Its Binding to Microtubules*

The results suggest that Ckiδ phosphorylates tau at sites that modulate tau/microtubule binding, and that the expression pattern of CKIδ in Alzheimer's disease is consistent with it playing an important role in tau aggregation.

Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro*

The data indicate that FTDP-17 missense mutations, by promoting phosphorylation at Ser202, inhibit the microtubule assembly-promoting activity of tau in vitro, suggesting that Ser202 phosphorylated plays a major role in the development of NFT pathology in AD and related tauopathies.

Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function

The present study identified a novel role of death-associated protein kinase 1 (DAPK1) in the regulation of the tau protein and found that hippocampal D APK1 expression is markedly increased in the brains of AD patients compared with age-matched normal subjects, suggesting that DAPK 1 might be a novel therapeutic target for treating human AD and other tau-related pathologies.

Pseudophosphorylation of tau modulates its function and induces AD-like changes

Pseudohyperphosphorylation mutants at six or sever GSK-3β phosphorylation sites were generated by amino acid substitution and changes on mobility on SDS-PAGE, microtubule (MT) binding and arachidonic acid (ARA) induced polymerization were studied.

Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease

It is determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn, adding new support for a role for fyn in the neurodegenerative process.

Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo

All these phospho-tau-mediated phenotypes occur in the absence of tau filament/neurofibrillary tangle formation or neuronal death, and may constitute the mechanism by which hyper-phosphorylated tau disrupts neuronal function and contributes to cognitive impairment prior to neuronal death in the early stages of t Tauopathies.

Detection of Phosphorylated Ser262 in Fetal Tau, Adult Tau, and Paired Helical Filament Tau (*)

It is speculated that the binding of tau to microtubules is regulated by phosphorylation at multiple sites and that the generation of PHF-tau in Alzheimer's disease results from the reduced efficiency of phosphatases leading to the incremental accumulation of hyperphosphorylated tau.
...

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The switch of tau protein to an Alzheimer‐like state includes the phosphorylation of two serine‐proline motifs upstream of the microtubule binding region.

It is shown that a new monoclonal antibody, AT8, records the PHF‐like state of tau in vitro, and a kinase activity is described that turns normal tau into a PHF-like state.

Regions with abundant neurofibrillary pathology in human brain exhibit a selective reduction in levels of binding-competent tau and accumulation of abnormal tau-isoforms (A68 proteins).

Quantitative immunoblot analysis provides compelling evidence that A68 proteins are generated from tau-proteins in selected regions of the AD brain where neurofibrillary lesions comprised of paired helical filaments accumulate.

A68: a major subunit of paired helical filaments and derivatized forms of normal Tau.

The major subunits of a class of PHFs are A68 proteins and the excessive or inappropriate phosphorylation of normal tau may change its apparent Mr, thus transforming tau into A68.

Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer‐like state.

It is proposed that MAP kinase is abnormally active in Alzheimer brain tissue, or that the corresponding phosphatases are abnormally passive, due to a breakdown of the normal regulatory mechanisms.

The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development.

  • M. GoedertR. Jakes V. Lee
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1993
It is shown here that Ser-202 (in the numbering of the longest human brain tau isoform) is a phosphorylation site that distinguishes fetal from adult tau and it is identified as one of the abnormal phosphorylated sites in Alzheimer disease.