P3-140: Decreased axonal transport during Alzheimer's-like spatial-temporal tau pathology leads to imbalance of NGF, cholinergic dysfunction, and decreased regulation of BDNF and TrkB

Tau protein is subject to phosphorylation by multiple kinases at more than 80 different sites. Some of these sites are associated with tau pathology and neurodegeneration, but other sites are modified in normal tau as well as in pathological tau. Although phosphorylation of tau at residues in the microtubule-binding repeats is thought to reduce tau association with microtubules, the functional consequences of other sites are poorly understood. The AT8 antibody recognizes a complex phosphoepitope site on tau that is detectable in a healthy brain but significantly increased in Alzheimer’s disease (AD) and other tauopathies. Previous studies showed that phosphorylation of tau at the AT8 site leads to exposure of an N-terminal sequence that promotes activation of a protein phosphatase 1 (PP1)/glycogen synthase 3 (GSK3) signaling pathway, which inhibits kinesin-1-based anterograde fast axonal transport (FAT). This finding suggests that phosphorylation may control tau conformation and function. However, the AT8 includes three distinct phosphorylated amino acids that may be differentially phosphorylated in normal and disease conditions. To evaluate the effects of specific phosphorylation sites in the AT8 epitope, recombinant, pseudophosphorylated tau proteins were perfused into the isolated squid axoplasm preparation to determine their effects on axonal signaling pathways and FAT. Results from these studies suggest a mechanism where specific phosphorylation events differentially impact tau conformation, promoting activation of independent signaling pathways that differentially affect FAT. Implications of findings here to our understanding of tau function in health and disease conditions are discussed.

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Drosophila modelling axonal transport in the face of tau pathology

SpringerPlus ◽

10.1186/2193-1801-4-s1-l13 ◽

2015 ◽

Vol 4 (S1) ◽

Author(s):

Amrit Mudher

Keyword(s):

Axonal Transport ◽

Tau Pathology ◽

The Face

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Emergence of directional bias in tau deposition from axonal transport dynamics

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009258 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009258

Author(s):

Justin Torok ◽

Pedro D. Maia ◽

Parul Verma ◽

Christopher Mezias ◽

Ashish Raj

Keyword(s):

Computational Model ◽

Axonal Transport ◽

Molecular Processes ◽

Tau Pathology ◽

Complex Interplay ◽

Directional Bias ◽

Neuron System ◽

Transport Dynamics ◽

Clinical Presentations ◽

Disease Specific

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.

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Emergence of directional bias in tau deposition from axonal transport dynamics

10.1101/2021.03.22.436470 ◽

2021 ◽

Author(s):

Justin Torok ◽

Pedro D Maia ◽

Parul Verma ◽

Christopher Mezias ◽

Ashish Raj

Keyword(s):

Computational Model ◽

Axonal Transport ◽

Molecular Processes ◽

Tau Pathology ◽

Complex Interplay ◽

Directional Bias ◽

Neuron System ◽

Transport Dynamics ◽

Clinical Presentations ◽

Disease Specific

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.

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Efficient propagation of misfolded tau between individual neurons occurs in absence of degeneration

10.1101/372029 ◽

2018 ◽

Author(s):

Grace I Hallinan ◽

Mariana Vargas-Caballero ◽

Jonathan West ◽

Katrin Deinhardt

Keyword(s):

Cell Death ◽

Axonal Transport ◽

Tau Protein ◽

Neuronal Death ◽

Early Event ◽

Neuronal Dysfunction ◽

Tau Pathology ◽

Functional Consequences ◽

Tau Aggregation ◽

The Brain

AbstractIn Alzheimer’s disease, misfolded tau protein propagates through the brain in a prion-like manner along connected circuits. Tauopathy correlates with significant neuronal death, but the links between tau aggregation, propagation, neuronal dysfunction and death remain poorly understood, and the direct functional consequences for the neuron containing the tau aggregates are unclear. Here, by monitoring individual neurons within a minimal circuit, we demonstrate that misfolded tau efficiently spreads from presynaptic to postsynaptic neurons. Within postsynaptic cells, tau aggregates initially in distal axons, while proximal axons remain free of tau pathology. In the presence of tau aggregates neurons display axonal transport deficits, but remain viable and electrically competent. This shows that misfolded tau species are not immediately toxic to neurons, and suggests that propagation of misfolded tau is an early event in disease, occurring prior to neuronal dysfunction and cell death.

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