Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain

Abstract

Tau pathology is known to spread in a hierarchical pattern in Alzheimer’s disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…Expression of GFP alone does not lead to droplets. Droplet dynamics in neurons is shown in Movie EV1.FRAP reveals incomplete recovery of droplet‐like tau in neuronal cell bodies indicating an immobile fraction of GFP‐tau441 molecules of ≈30%.Neurons growing in microfluidic chambers extend their axons in microgrooves (Takeda et al , 2015). Time‐lapse imaging (#1–5, time interval ≈3 s) shows the movement of droplet‐like GFP‐tau441 (white arrows) in axons over time.…”

“…Neurons growing in microfluidic chambers extend their axons in microgrooves (Takeda et al , 2015). Time‐lapse imaging (#1–5, time interval ≈3 s) shows the movement of droplet‐like GFP‐tau441 (white arrows) in axons over time.…”

“…We previously showed that high molecular weight tau species, which are hyperphosphorylated and presumably oligomeric in nature, are bioactive for neuronal uptake and templated misfolding (Takeda et al , 2015). …”

“…It is clear, for example, that post‐translational modifications (PTMs) and tau mutations predisposing to aggregation are both associated with neurodegeneration. Recently, soluble hyperphosphorylated high molecular weight tau was identified as a bioactive form, which can be released and taken up by neurons and initiate templated misfolding of cytoplasmic tau in neurons (Takeda et al , 2015). This soluble hyperphosphorylated tau is, however, clearly distinct from aggregated fibrillary tau in neurofibrillary tangles, despite both being implicated in tau toxicity.…”

3D Miniaturization of Human Organs for Drug Discovery

“…[70] Takeda et al also developed a novel neural network culture technique to mimic the layered structure of cerebral cortex by controlling the positions of somata and the direction of neurite outgrowth on the basis of the groove guide connected through three compartment chambers ( Figure 7D). [71] This 3D heterogeneous neural component allows the visualization of the network of two different neural connections and was used to assess tau propagation in Alzheimer's disease. Tau spreads in a hierarchical pattern in AD brain during disease progression, likely by trans-synaptic tau transfer between neurons.…”