A Receptor That Lets Dementia-Associated Tau Proteins Into Neurons

A study in Nature identified a cell-surface receptor that enables the dementia-associated tau protein to move between neurons — offering a clue on the mechanism of its spread within the brain. The researchers speculated whether a member of the low-density-lipoprotein receptor (LDLR) protein family could be critical to tau's proliferation — and demonstrated that the loss of LRP1 lowered tau internalization into neurons, and disrupted the internalization of all forms of soluble, physiological tau and of aggregating clumps of pathological tau. The implication is that LRP1 could mediate the transfer of both physiological and pathological tau. Moreover, LRP1 loss only partially impeded the uptake of larger "fibril fragments" of tau, although these fragments also might be internalized through less specific engulfing mechanisms that occur in neurons. Further, tau competes with known LRP1 partners, including the lipid transporter ApoE, for binding to LRP1. The researchers plotted out the areas of tau and LRP1 that interact, finding two domains in the portion of LRP1 located outside the cell, and a series of lysine amino-acid residues in tau that are exposed on the pathogenic protein. Targeting these residues via chemical inactivation blocked neuronal tau uptake. This could potentially enable the design of molecules that target tau to combat its propagation.