Abstract
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.
Recommended Citation
D. B. Hier et al., "Tau Kinetics in Alzheimer's Disease," Frontiers in Aging Neuroscience, vol. 14, article no. 1055170, Frontiers Media, Nov 2022.
The definitive version is available at https://doi.org/10.3389/fnagi.2022.1055170
Department(s)
Chemistry
Second Department
Biological Sciences
Third Department
Electrical and Computer Engineering
Keywords and Phrases
Alzheimer's disease; clearance; CSF levels; halflife; plasma levels; steady state kinetics; tau; turnover
International Standard Serial Number (ISSN)
1663-4365
Document Type
Article - Journal
Document Version
Final Version
File Type
text
Language(s)
English
Rights
© 2023 The Authors, All rights reserved.
Creative Commons Licensing
This work is licensed under a Creative Commons Attribution 4.0 License.
Publication Date
09 Nov 2022
Comments
National Science Foundation, Grant W911NF-14-2-0034