Emergence of directional bias in tau deposition from axonal transport dynamics.

Autor: Torok J; Department of Computational Biology and Medicine, Weill Cornell Medical School, New York, New York, United States of America., Maia PD; Department of Mathematics, University of Texas at Arlington, Arlington, Texas, United States of America., Verma P; Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, California, United States of America., Mezias C; Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, California, United States of America., Raj A; Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, California, United States of America.
Jazyk: angličtina
Zdroj: PLoS computational biology [PLoS Comput Biol] 2021 Jul 27; Vol. 17 (7), pp. e1009258. Date of Electronic Publication: 2021 Jul 27 (Print Publication: 2021).
DOI: 10.1371/journal.pcbi.1009258
Abstrakt: Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer's disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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