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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2022.1055170/full |
| _version_ | 1828199359872761856 |
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| author | Daniel B. Hier Daniel B. Hier Sima Azizi Matthew S. Thimgan Donald C. Wunsch Donald C. Wunsch |
| author_facet | Daniel B. Hier Daniel B. Hier Sima Azizi Matthew S. Thimgan Donald C. Wunsch Donald C. Wunsch |
| author_sort | Daniel B. Hier |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T10:55:11Z |
| format | Article |
| id | doaj.art-178188a12d1842128fcf139dc5604c33 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-04-12T10:55:11Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-178188a12d1842128fcf139dc5604c332022-12-22T03:36:07ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652022-11-011410.3389/fnagi.2022.10551701055170Tau kinetics in Alzheimer's diseaseDaniel B. Hier0Daniel B. Hier1Sima Azizi2Matthew S. Thimgan3Donald C. Wunsch4Donald C. Wunsch5Applied Computational Intelligence Laboratory, Department of Electrical & Computer Engineering, Missouri University of Science & Technology, Rolla, MO, United StatesDepartment of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL, United StatesApplied Computational Intelligence Laboratory, Department of Electrical & Computer Engineering, Missouri University of Science & Technology, Rolla, MO, United StatesDepartment of Biological Sciences, Missouri University of Science & Technology, Rolla, MO, United StatesApplied Computational Intelligence Laboratory, Department of Electrical & Computer Engineering, Missouri University of Science & Technology, Rolla, MO, United StatesECCS Division, National Science Foundation, Alexandria, VA, United StatesThe 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.https://www.frontiersin.org/articles/10.3389/fnagi.2022.1055170/fulltauAlzheimer's diseaseCSF levelsplasma levelssteady state kineticshalflife |
| spellingShingle | Daniel B. Hier Daniel B. Hier Sima Azizi Matthew S. Thimgan Donald C. Wunsch Donald C. Wunsch Tau kinetics in Alzheimer's disease Frontiers in Aging Neuroscience tau Alzheimer's disease CSF levels plasma levels steady state kinetics halflife |
| 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 | tau Alzheimer's disease CSF levels plasma levels steady state kinetics halflife |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2022.1055170/full |
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