Neurofibrillary tangles (NFTs) are one of the characteristic features of Alzheimer disease (AD) neuropathology. They are made primarily of the microtubule associated protein tau (MAPT) that is highly phosphorylated, mislocalized to the cytoplasm from the axon, and aggregated in a complex, dense −pleated sheet that are paired helical filaments (PHFs) as determined by cryo-electron microscopy. The distribution of NFTs in the brain is overwhelmingly consistent across cases of AD: NFT occur initially in the entorhinal cortex, then “spread” to other limbic and association areas over more than a decade; this spread corresponds to the clinical symptoms of the disease, and correlates with neuronal loss. It was recognized early on that the pattern of spread largely followed neuroanatomical connections, and it was demonstrated that at least part of the reason for this could be explained by propagation of misfolded tau across synaptic elements. Recently, it has been discovered that the LDL receptor-related protein binds tau and participates in tau propagation. The Hyman and Strickland laboratories have worked together on LRP1 related projects since 1993 and have collaborated to confirm these observations. Using fractions isolated from AD patient brains, we confirm that LRP1-expressing cells, but not LRP1-deficient cells, promote tau seeding, demonstrating that LRP1 mediated uptake can lead to escape of tau proteopathic seeds into the cytoplasm. The mechanism(s) of how this occurs are currently not known and will be investigated in Aims 1 and 3 of this grant. We also identified some residual uptake that we now show to be due, in part, to SORL1, another apoE receptor that is implicated in trafficking, and – importantly- is also clearly implicated in the genetics of AD. The role of SORL1 in tau uptake and processing will be examined in Aims 2 and 3). These data and new questions lead us to propose a multi-PI application to explore the following aims: (1) Identify mechanisms by which LRP1 promotes proteopathic seeding of tau; (2) Define the contribution of SORL1 and SORL1 mutants to tau proteopathic seeding; (3) Identify mechanisms responsible for the endolysosomal escape and tau seeding
