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Tau kinetics in Alzheimer's disease

The cytoskeletal protein tau is implicated in the pathogenesis of Alzheimer's disease which is characterized by intra-neuronal neurofibrillary tangles containing abnormally phosphorylated insoluble tau. Levels of soluble tau are elevated in the brain, the CSF, and the plasma of patients with Al...

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Autores principales: Hier, Daniel B., Azizi, Sima, Thimgan, Matthew S., Wunsch, Donald C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9682289/
https://www.ncbi.nlm.nih.gov/pubmed/36437992
http://dx.doi.org/10.3389/fnagi.2022.1055170
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author Hier, Daniel B.
Azizi, Sima
Thimgan, Matthew S.
Wunsch, Donald C.
author_facet Hier, Daniel B.
Azizi, Sima
Thimgan, Matthew S.
Wunsch, Donald C.
author_sort Hier, Daniel B.
collection PubMed
description The cytoskeletal protein tau is implicated in the pathogenesis of Alzheimer's disease which is characterized by intra-neuronal neurofibrillary tangles containing abnormally phosphorylated insoluble tau. Levels of soluble tau are elevated in the brain, the CSF, and the plasma of patients with Alzheimer's disease. To better understand the causes of these elevated levels of tau, we propose a three-compartment kinetic model (brain, CSF, and plasma). The model assumes that the synthesis of tau follows zero-order kinetics (uncorrelated with compartmental tau levels) and that the release, absorption, and clearance of tau is governed by first-order kinetics (linearly related to compartmental tau levels). Tau that is synthesized in the brain compartment can be released into the interstitial fluid, catabolized, or retained in neurofibrillary tangles. Tau released into the interstitial fluid can mix with the CSF and eventually drain to the plasma compartment. However, losses of tau in the drainage pathways may be significant. The kinetic model estimates half-life of tau in each compartment (552 h in the brain, 9.9 h in the CSF, and 10 h in the plasma). The kinetic model predicts that an increase in the neuronal tau synthesis rate or a decrease in tau catabolism rate best accounts for observed increases in tau levels in the brain, CSF, and plasma found in Alzheimer's disease. Furthermore, the model predicts that increases in brain half-life of tau in Alzheimer's disease should be attributed to decreased tau catabolism and not to increased tau synthesis. Most clearance of tau in the neuron occurs through catabolism rather than release to the CSF compartment. Additional experimental data would make ascertainment of the model parameters more precise.
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spelling pubmed-96822892022-11-24 Tau kinetics in Alzheimer's disease Hier, Daniel B. Azizi, Sima Thimgan, Matthew S. Wunsch, Donald C. Front Aging Neurosci Aging Neuroscience The cytoskeletal protein tau is implicated in the pathogenesis of Alzheimer's disease which is characterized by intra-neuronal neurofibrillary tangles containing abnormally phosphorylated insoluble tau. Levels of soluble tau are elevated in the brain, the CSF, and the plasma of patients with Alzheimer's disease. To better understand the causes of these elevated levels of tau, we propose a three-compartment kinetic model (brain, CSF, and plasma). The model assumes that the synthesis of tau follows zero-order kinetics (uncorrelated with compartmental tau levels) and that the release, absorption, and clearance of tau is governed by first-order kinetics (linearly related to compartmental tau levels). Tau that is synthesized in the brain compartment can be released into the interstitial fluid, catabolized, or retained in neurofibrillary tangles. Tau released into the interstitial fluid can mix with the CSF and eventually drain to the plasma compartment. However, losses of tau in the drainage pathways may be significant. The kinetic model estimates half-life of tau in each compartment (552 h in the brain, 9.9 h in the CSF, and 10 h in the plasma). The kinetic model predicts that an increase in the neuronal tau synthesis rate or a decrease in tau catabolism rate best accounts for observed increases in tau levels in the brain, CSF, and plasma found in Alzheimer's disease. Furthermore, the model predicts that increases in brain half-life of tau in Alzheimer's disease should be attributed to decreased tau catabolism and not to increased tau synthesis. Most clearance of tau in the neuron occurs through catabolism rather than release to the CSF compartment. Additional experimental data would make ascertainment of the model parameters more precise. Frontiers Media S.A. 2022-11-09 /pmc/articles/PMC9682289/ /pubmed/36437992 http://dx.doi.org/10.3389/fnagi.2022.1055170 Text en Copyright © 2022 Hier, Azizi, Thimgan and Wunsch. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Aging Neuroscience
Hier, Daniel B.
Azizi, Sima
Thimgan, Matthew S.
Wunsch, Donald C.
Tau kinetics in Alzheimer's disease
title Tau kinetics in Alzheimer's disease
title_full Tau kinetics in Alzheimer's disease
title_fullStr Tau kinetics in Alzheimer's disease
title_full_unstemmed Tau kinetics in Alzheimer's disease
title_short Tau kinetics in Alzheimer's disease
title_sort tau kinetics in alzheimer's disease
topic Aging Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9682289/
https://www.ncbi.nlm.nih.gov/pubmed/36437992
http://dx.doi.org/10.3389/fnagi.2022.1055170
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