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

Shuko Takeda,Isabel Costantino,George A Carlson,Daniel Irimia,Chloe K Nobuhara,Daniel J Müller,Bradley T Hyman,Allyson D Roe,Hansang Cho,Caitlin Commins,Samantha B Nicholls,Matthew P Frosch,Sarah L Devos,Rose Pitstick,Susanne Wegmann

doi:10.1038/ncomms9490

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.

Highlights

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
By developing the rTgTauEC mouse model of early AD that overexpresses human mutant P301L tau selectively in the entorhinal cortex (EC), we and other groups have demonstrated that aggregated tau accumulates in synaptically connected downstream areas such as dentate gyrus, suggesting that neurofibrillary tangles (NFTs) propagation occurs by cross-synaptic spread of pathologically misfolded tau proteins[9,10,11,12]
Identifying the tau species that can be transferred between neurons is essential for understanding mechanisms by which misfolded tau propagates in AD and other tauopathies

Summary

Introduction

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. The precise mechanisms for this characteristic tau pathology spread remain unknown, accumulating evidence suggests a trans-synaptic transfer of tau proteins between neurons[6,7,8]. By developing the rTgTauEC mouse model of early AD that overexpresses human mutant P301L tau selectively in the EC, we and other groups have demonstrated that aggregated tau accumulates in synaptically connected downstream areas such as dentate gyrus, suggesting that NFT propagation occurs by cross-synaptic spread of pathologically misfolded tau proteins[9,10,11,12]. Our findings suggest that PBS-soluble phosphorylated HMW tau species, present in the brain extracellular space, are involved in neuronal uptake and propagation

Methods

Results

Conclusion