Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism
AuthorCooper, Joanna M
Arai, Allison L
Wani, Mashhood M
Muratoglu, Selen C
Hyman, Bradley T
Strickland, Dudley K
JournalJournal of Biological Chemistry
MetadataShow full item record
AbstractIn Alzheimer's disease (AD), pathological forms of tau are transferred from cell to cell and "seed" aggregation of cytoplasmic tau. Phosphorylation of tau plays a key role in neurodegenerative tauopathies. In addition, apolipoprotein E (apoE), a major component of lipoproteins in the brain, is a genetic risk determinant for AD. The identification of the apoE receptor, LRP1, as an endocytic receptor for tau raises several questions about LRP1's role in tauopathies: is internalized tau, like other LRP1 ligands, delivered to lysosomes for degradation and does LRP1 internalize pathological tau leading to cytosolic seeding? We found that LRP1 rapidly internalizes 125I-labeled tau, which is then efficiently degraded in lysosomal compartments. Surface plasmon resonance experiments confirm high affinity binding of tau and the tau microtubule binding domain to LRP1. Interestingly, phosphorylated forms of recombinant tau bind weakly to LRP1 and are less efficiently internalized by LRP1. LRP1-mediated uptake of tau is inhibited by apoE, with the apoE4 isoform being the most potent inhibitor, likely due to its higher affinity for LRP1. Employing post translationally modified tau derived from brain lysates of human AD brain tissue, we found that LRP1-expressing cells, but not LRP1-deficient cells, promote cytosolic tau seeding in a process enhanced by apoE. These studies identify LRP1 as an endocytic receptor that binds and processes monomeric forms of tau leading to its degradation and promotes seeding by pathological forms of tau. The balance of these processes may be fundamental to spread of neuropathology across the brain in Alzheimer's disease.
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Low Density Lipoprotein Receptor-Related Protein 1
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/15591