Abstract
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.
Highlights
Despite manifest differences in clinical presentation, the pathology of many progressive neurodegenerative diseases is linked to aberrant protein misfolding and aggregation
We propose that the conformer-specific dysregulation of axonal transport can lead to directionally biased spread, and we employ a mathematical model to explore how tau spreads between neurons in the context of this transport feedback mechanism
Recent work by our group has lent further support for this hypothesis, wherein we found that mouse tauopathy models with tau species that developed in the presence of amyloid-β showed a marked preference to migrate in the retrograde direction, while no consensus directional bias emerged among amyloid-negative models [20]
Summary
Despite manifest differences in clinical presentation, the pathology of many progressive neurodegenerative diseases is linked to aberrant protein misfolding and aggregation. In Alzheimer’s disease (AD) [1], frontotemporal lobar degeneration (FTLD) [2], Parkinson’s disease [3], Huntington disease [4], and in amyotrophic lateral sclerosis [5], there are one or more proteinaceous species that appear to spread throughout the brain and induce neuronal dysfunction and death Both in vitro experiments with cultured neurons [6,7,8,9,10] and in vivo work with animal models of neurodegeneration [11,12,13] have confirmed that these prion-like assemblies can spread directly between neurons by traveling within axonal fibers and traversing the synapse. There are no models to date that explore how this directional bias arises
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