LRP1 mediates tau endocytosis in a process that is modulated by apolipoprotein E

Background Cognitive decline in Alzheimer’s disease correlates with the spreading of neurofibrillary tangles consisting of aggregated forms of tau from the entorhinal cortex to synaptically connected brain regions. It is unclear how tau aggregation propagates across the brain but may involve trans‐synaptic transfer of tau between neurons or uptake of extracellular tau that is constitutively secreted from neurons. Specific receptors involved in these processes have remained elusive, and here we investigate the hypothesis that the LDL receptor‐related protein 1 (LRP1) functions as an endocytic receptor for tau. Method We employed 125I‐labeled tau to quantify its cellular uptake, confocal microscopy to examine its colocalization with LRP1, and surface plasmon resonance to assess direct binding of tau and phosphorylated forms of tau to LRP1. Result Our results reveal that monomeric tau binds LRP1 with high affinity, while curiously, phosphorylated forms of tau bind LRP1 with much lower affinity. The studies confirm that LRP1 internalization is attenuated the LRP1 antagonist RAP and is reduced by 70% in LRP1‐deficient cells. Confocal microscopy reveals that internalized tau colocalizes with LRP1 in endocytic vesicles. Most of the LRP1‐mediated uptake of tau leads to its lysosomal degradation. We also demonstrate that apolipoprotein E (ApoE) inhibits LRP1‐mediated tau internalization, with the ApoE4 isoform being a more potent inhibitor than other ApoE isoforms. Our studies in LRP1‐deficient cell lines confirm that a RAP‐insensitive second internalization mechanism occurs for tau, suggesting the existence of an LRP1‐independent receptor‐mediated process for tau uptake. Conclusion LRP1 functions as an endocytic receptor for tau, mediating the uptake of monomeric forms of tau resulting in its degradation. The ability of ApoE4 to modulate LRP1‐mediated uptake of tau may disrupt the normal physiological process of tau catabolism, leading to tau uptake by other mechanisms causing the spreading of neurofibrillary tangles and exacerbating the progression of tau‐mediated cognitive loss.