Investigating the binding of high molecular weight tau to LRP1

The spread of neurofibrillary tangle (NFT) pathology across the brain is a hallmark of Alzheimer’s disease (AD) and is thought to be driven by the cell‐to‐cell transport of seed competent tau protein. LRP1 is a receptor for tau that mediates tau uptake, degradation, and seeding of intracellular tau aggregation. We previously found that LRP1 binds recombinantly produced 2N4R tau with high affinity, and that phosphorylation on tau reduces its affinity for LRP1. However, it is unknown if LRP1 interacts with the soluble HMW forms of tau that drive tau seeding, and here we investigate LRP1 binding to HMW phospho‐mimetic tau or HMW tau isolated from AD patient brains.