Extracellular Tau Oligomers Induce Disruption of Endogenous Tau Distribution, Invasion of Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction 950 views

Insoluble hyperphosphylated aggregates of the microtubule-associated protein tau define a subset of neurodegenerative disorders known as tauopathies, of which Alzheimer’s Disease is the most prevalent. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks, in a manner that recapitulates the temporal spread of pathology observed upon post-mortem analysis of diseased tissue. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill-defined as do the consequences of intracellular tau aggregation on neuronal physiology. The work in the dissertation presented here was undertaken to compare the effects of extracellular tau monomers, oligomers and filaments comprising various tau isoforms on the behavior of cultured neurons. This work demonstrates that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all 6 isoforms most potently provoked focal, intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Preliminary data indicate that this somatodendritic tau accumulation may be due to disruption of ankyrin G and βIV spectrin, key components of the axon initial segment. Finally, this work shows that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo, and these alterations in fast axonal transport were diminished in neurons not expressing tau. This work provides a more physiological model of tau uptake in neurons and indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering focal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport. Additionally, by identifying species involved in cellular dysfunction, it provides a target for much needed future therapies in AD and non-AD tauopathies.

PHD (Doctor of Philosophy)

Alzheimer's Disease; Tau Prrotein; Prion-like aspects of neurodegeneration

English

2017-04-29