Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

Abstract

Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer’s disease and non-Alzheimer’s tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. 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, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found 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 six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed 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. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport.

Dendritic Tau in Alzheimer’s Disease

“…Seeds of trans-synaptically transferred tau would make first contact with post-synaptic tau within receiving neurons, raising the intriguing concept that post-synaptic tau is the primary target for prion-like spreading of tau pathology, including possibly localized oligomerization of tau. Consistent with this idea, exposure to extracellular tau promoted recruitment of endogenous tau into dendrites (Swanson et al, 2017). Other post-synaptic processes may further contribute to trans-synaptic spread of tau pathology; for example, neuronal activity was shown to promote spread of tau pathology in vivo and in vitro (Calafate et al, 2015;Wu et al, 2016).…”

“…Specifically, this study used expression of a dominant-negative tau variant and tau depletion in mice to reveal how endogenous tau mediates post-synaptic signals in Ab toxicity. Subsequent studies confirmed that endogenous tau localizes to dendrites and post-synapses in rodent neurons, using immune-labeling, synaptosomal fractionation, and ultrastructural analysis approaches (Ittner et al, 2010(Ittner et al, , 2016Kimura et al, 2013;Mondragó n-Rodríguez et al, 2012;Swanson et al, 2017;Zempel et al, 2013). Furthermore, mice genetically engineered to express endogenous tau with a C-terminally fused mEOS2 fluorescent reporter showed that endogenous murine tau localizes to dendritic spines (Xia et al, 2016).…”

Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms

“…The dependence of axons on proper anterograde and retrograde AT is evident because mutations in selected conventional kinesins or cytoplasmic dynein subunits suffice to promote dying-back degeneration of neurons (Morfini et al, 2009 ). Providing an explanation for the axonal degeneration phenotype observed in tauopathies, multiple independent studies documented deficits in AT triggered by pathogenic forms of tau, including oligomeric tau (Higuchi et al, 2005 ; Gotz et al, 2006 ; Cox et al, 2016 ; Swanson et al, 2017 ). Several mechanisms are proposed to mediate this toxic effect.…”

Human Tau Isoform Aggregation and Selective Detection of Misfolded Tau from Post-Mortem Alzheimer’s Disease Brains

“…In this study, we produced all six recombinant human tau isoforms that are as aggregationcompetent to form oligomers and mature filaments as those in AD and other tauopathies (Swanson et al, 2017). We dissected the key segments in tau isoforms contributing to their aggregation.…”