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

• DOI: 10.1038/ncomms9490
• Publication Date: 2015-10-13T10:12:14Z
• Authors: Shuko Takeda; Susanne Wegmann; Hansang Cho; Sarah L. DeVos; Caitlin Commins; Allyson D. Roe; Samantha B. Nicholls; George A. Carlson; Rose Pitstick; Chloe K. Nobuhara; Isabel Costantino; Matthew P. Frosch; Daniel J. Müller; Daniel Irimia; Bradley T. Hyman
• Keywords: Aged, 80 and over; Male; Neurons; 0303 health sciences; Cell Survival; 610; Brain; Mice, Transgenic; tau Proteins; Microfluidic Analytical Techniques; Article; 3. Good health; Mice, Inbred C57BL; 03 medical and health sciences; HEK293 Cells; Alzheimer Disease; Animals; Humans; Female; Phosphorylation; Aged

AbstractTau 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.