LRP1 : A Novel Mediator of Tau Uptake

Autor: Maria Stamelou, Günter U. Höglinger, Amir Tayaranian Marvian
Rok vydání: 2020
Předmět:
Zdroj: Movement disorders 35(7), 1136-1136 (2020). doi:10.1002/mds.28107
ISSN: 1531-8257
0885-3185
DOI: 10.1002/mds.28107
Popis: Propagation of intracellular tau inclusions is found to be associated with the progress of symptoms in various neurodegenerative diseases.1 A growing body of evidence suggests that tau pathology spreads via a prion‐like mechanism, through which cell‐to‐cell transfer of pathogenic tau species seeds new aggregates by the recruitment of normal endogenous tau.2 One of the crucial steps in this process is the uptake of tau seeds from the extracellular environment. The uptake of tau monomers and aggregates has been observed in many in vitro and in vivo models; however, the cellular and molecular mechanisms of this phenomenon were still elusive.In a recent study, Rauch and colleagues3 identified for the first time a membrane protein to interact directly with tau and to be involved in the process of tau uptake from the extracellular compartment into neurons. Clustered regularly interspaced short palindromic repeats interference technology was used to knockdown 7 various members of the low‐density lipoprotein receptor family. Among them, only the repression of lipoprotein receptor‐related protein 1 (LRP1) completely blocked the uptake of monomeric and oligomeric tau, whereas the uptake of fibrillar tau was partially inhibited. These results suggest that the uptake mechanism of monomeric and oligomeric tau is similar; however, the uptake of tau fibrils may involve other pathways. The substantial reduction of tau uptake upon treatment with the receptor‐binding protein as an LRP1 antagonist further confirmed the role of LRP1 in tau uptake. Examining the uptake of different isoforms and fragments of tau indicated that LRP1‐mediated tau uptake mainly depends on the presence of the microtubule‐binding domain of tau. Further combinational analysis elucidates the interaction of lysine residues in microtubule‐binding domain of tau with LRP1. Finally, an in vivo study revealed that the spread of tau is vastly reduced in short hairpin RNA‐mediated LRP1‐knockout mice.Previously, heparan‐sulfate proteoglycans have been shown to be involved in the uptake of tau monomers and aggregates.4 However, heparan‐sulfate proteoglycans are highly interacting harbors for many different targets on the cell surface and are not specifically interacting with tau. The cooperation of LRP1 and heparan‐sulfate proteoglycans has been reported in the neuronal uptake of Aβ,5 suggesting the similarity between the cellular uptake mechanisms of Aβ and tau. The incomplete uptake blockage of tau fibrils and N‐terminus tau fragments following the repression of LRP1 suggests the possible role of other uptake mechanisms in tau spreading, although the actual seeding species of tau in this process is still unknown. The knockdown of LRP1 inhibited the uptake of different monomeric tau isoforms including 3R and 4R tau in the same manner, suggesting that tau uptake mediated by LRP1 is not a discriminating factor among various types of tauopathies. Moreover, it would be of interest to explore whether polymorphisms in the LRP1 gene alter the risk of developing tauopathies. Thus, the exciting results of this study introduce a new molecular target for developing therapeutic strategies against tau spreading in the brains of patients suffering from tauopathies, including Alzheimer’s disease, progressive supranuclear palsy, and corticobasal degeneration.
Databáze: OpenAIRE
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