IDENTIFICATION OF TAU RECEPTOR TAU-RN FOR NEURONAL UPTAKE AND PROPAGATION OF OLIGOMERIC TAU

Abstract

Accumulation of intracellular tau inclusions is one of the pathological hallmarks in Alzheimer's disease (AD). In AD, distribution of neurofibrillary tangles (NFTs) changes during disease progression, starting in the entorhinal cortex and spreading throughout the neocortex. Misfolded tau is known to spread via prion-like propagation, physically moving from neuron to neuron and inducing seeded fibrillization. Especially, an oligomeric tau, other than monomer or fibril form, is considered as a pathogenic tau that can function as a seed. However, the mechanism how oligomeric tau is internalized into neurons for neuronal propagation remains unclear. Cell-based functional screening was performed using transmembrane cDNA expression library. Cells were transfected with cDNA clones and incubated with fluorescence-labeled tau oligomers. Tau uptake was measured using intracellular fluorescence intensity. For in vivo tau uptake assay, stereotaxic surgery was performed to inject tau transgenic mouse (rTg4510 or TauC3) brain extract into mouse frontal cortex or hippocampus. The mouse was then perfused and brain frozen section was prepared to assess neuronal tau uptake using immunohistochemistry or immunofluorescence assay. We developed a cell-based tau uptake screening assay and identified an oligomeric tau receptor, Tau-Rn. Overexpression of Tau-Rn increased cellular uptake of oligomeric tau in a dose-dependent manner and blocking clathrin-mediated endocytosis diminished Tau-Rn-mediated tau uptake. Compared to wild-type neurons, tau uptake was significantly reduced in the primary Tau-Rn knockout cortical neurons and in the Tau-Rn knockout mouse frontal cortex following the stereotaxic injection of tau transgenic mouse (rTg4510) brain extracts. In the pathogenic tau transgenic AD mouse model (TauC3), a blockade of Tau-Rn using its specific antagonist reduced tau pathology in the hippocampus. These results suggest that Tau-Rn plays an essential role in neuronal uptake of the pathogenic tau possibly for neuronal propagation, providing a mechanism underlying disease progression and new target for AD therapeutics.