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    Home > Active Ingredient News > Study of Nervous System > Nature. A new therapeutic target for the treatment of Tau protein-related neurodegenerative diseases, LDL-associated protein 1.

    Nature. A new therapeutic target for the treatment of Tau protein-related neurodegenerative diseases, LDL-associated protein 1.

    • Last Update: 2020-07-22
    • Source: Internet
    • Author: User
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    Chen Wenqiang (postdoctoral of Harvard Medical School) is responsible for the development of neurodegenerative diseases. An important event in the progress of neurodegenerative diseases is the diffusion of protein polymers.more and more evidence shows that the microtubule associated protein tau plays an important role in the pathogenesis of various forms of dementia, including Alzheimer's disease [1].these diseases are characterized by the sequential transmission and deposition of protein polymers, which are related to the severity of the disease.however, the cellular biological mechanism of tau protein transmission is still unclear.on April 1, 2020, the Kenneth Kosik research group from the University of California, Santa Barbara, USA, published an online publication entitled LRP1 is a master regulator of tau uptake and In the research paper of spread, we reported that low density lipoprotein associated protein 1 (LRP1) can control tau protein endocytosis and subsequent diffusion, and identified LRP1 as a key factor in regulating tau protein diffusion. The results suggest that LRP1 can be an important target for the treatment of diseases related to tau protein diffusion and aggregation.first of all, in order to study whether low-density lipoprotein receptor (LDLR) family members can affect tau protein endocytosis, the CRISPR interference technique (crispri) at cell line level was used to study the effect of inhibiting the expression of different LDLR family members on tau protein endocytosis. It was found that inhibition of LRP1 expression almost completely blocked tau protein uptake (Fig. 1).Fig. 1. Tau protein uptake mediated by LRP1. In order to further verify the results of LRP1 knockdown in cell lines, the point mutation of rap residues of the known LRP1 binding protein receptor associated protein (RAP) was studied.at the same time, in order to study how tau protein interacts with LRP1, the crystal structure of LDLR family members and their ligands was studied.the structures of these studies confirmed the important role of lysine residues in the interaction between tau protein and LRP1.because LRP1 contains four major ligand binding regions (Fig. 2C), in order to study which of these regions can affect tau protein uptake, different extracellular fragments were designed to study whether a single sub segment can rescue the endocytosis effect of tau protein in LRP1 knockdown cell lines.the researchers found that the sub fragment mlrp4 could completely rescue tau protein endocytosis (Fig. 2D), which was confirmed by further immunoprecipitation experiments.these results suggest that mlrp4 is the main interaction region of tau protein uptake.Fig. 2. The interaction between tau protein and LRP1 is normal, and LRP1 is mainly expressed in the post synaptic density [2], and previous studies have suggested that tau protein can be transmitted through the trans synaptic mechanism in vivo.therefore, the next question the researchers want to answer is whether tau protein can be regulated by LRP1 in neurons? The researchers used CRISPR interference technology again to knock down LRP1 expression in neurons induced by human derived pluripotent stem cells, and found that LRP1 knockdown significantly reduced the endocytosis effect of tau protein.this conclusion was further confirmed by morphological staining and flow cytometry (Fig. 3).Figure 3. LRP1 mediates tau protein uptake in neurons. Finally, the question the researchers want to answer is whether LRP1 plays a key role in the transmission of tau protein in the brain? The AAV vector was designed to effectively distinguish between neurons infected with human tau protein and neurons receiving human tau protein through transmission.the researchers used AAV carrying shRNA targeting LRP1- PHP.eB The LRP1 expression was knocked down, and then aav-gfp-p2a-htau was injected into the hippocampus. Through the cell count of htau + / GFP -, the transmission of tau protein in LRP1 knockdown mice was significantly reduced. Fig. 4. In vivo knockdown of LRP1 can effectively reduce the transmission of tau protein. In short, this study identified LRP1 as an important regulator of tau protein endocytosis in neurons. At the same time, it was also found that LRP1 also played an important role in the transmission of tau protein in the brain, which showed that the transmission of tau protein was significantly reduced after LRP1 knockdown. therefore, this study provides a new therapeutic target for tau related neurodegenerative diseases. references 1. Goedert m, eisenburg DS, and Crowther RA. Propagation of tau aggregates and neurogenesis. Ann. Rev. Neurosci. 40, 189 – 210 (2017). 2. Andersen om & amp; willnow te. Lipoprotein receptors in Alzheimer's disease. Trends Neurosci 29, 687 – 694 (2006)
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