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

• Published in: Nature communications Vol. 6; no. 1; p. 8490
• Main Authors: Takeda, Shuko, Wegmann, Susanne, Cho, Hansang, DeVos, Sarah L., Commins, Caitlin, Roe, Allyson D., Nicholls, Samantha B., Carlson, George A., Pitstick, Rose, Nobuhara, Chloe K., Costantino, Isabel, Frosch, Matthew P., Müller, Daniel J., Irimia, Daniel, Hyman, Bradley T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.10.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 13; 13/1; 631/378/1689/1283; 631/80/128/1653; 64; 64/60; 82; 82/1; 82/29; 82/51; 82/62; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Biosensors; Brain - metabolism; Brain research; Cell Survival; Disease; Female; HEK293 Cells; Humanities and Social Sciences; Humans; Male; Mice, Inbred C57BL; Mice, Transgenic; Microfluidic Analytical Techniques; Molecular weight; multidisciplinary; Neurons; Neurons - metabolism; Pathology; Phosphorylation; Propagation; Rare species; Science; Science (multidisciplinary); tau Proteins - metabolism; United States > US; Massachusetts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9490

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. In Alzheimer's disease, tau spreads throughout the brain, however the nature of the tau species propagating from one neuron to another is not known. Here, Takeda et al . identify a rare, high-molecular-weight tau as the primary species taken up and transferred between synaptically connected neurons.