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• W4313894092 endingPage "853" @default.
• W4313894092 startingPage "853" @default.
• W4313894092 abstract "Cellular internalization and the spreading of misfolded tau have become increasingly important for elucidating the mechanism of Tau pathology involved in Alzheimer’s disease (AD). The low-density lipoprotein-related receptor 1 (LRP1) has been implicated in the internalization of fibrillar tau. In this work, we utilized homology modeling to model the Cluster 2 domain of LRP1 and determined that a 23-amino-acid sequence is involved in binding to paired helical filaments (PHF) of Tau. Fourteen short peptide segments derived from this ectodomain region were then designed and docked with PHF Tau. Molecular dynamics studies of the optimal peptides bound to PHF Tau demonstrated that the peptides formed critical contacts through Lys and Gln residues with Tau. Based on the computational results, flow cytometry, AFM, SPR analysis and CD studies were conducted to examine binding and cellular internalization. The results showed that the peptide sequence TauRP (1–14) (DNSDEENCES) was not only associated with fibrillar Tau but was also able to mitigate its cellular internalization in LRP1-expressed HEK-293 cells. Preliminary docking studies with Aβ (1–42) revealed that the peptides also bound to Aβ (1–42). While this study focused on the CCR2 domain of LRP1 to design peptide sequences to mitigate Tau internalization, the work can be extended to other domains of the LRP1 receptor or other receptors to examine if the cellular internalization of fibrillar Tau can be deterred. These findings show that short peptides derived from the LRP1 receptor can alter the internalization of its ligands." @default.
• W4313894092 created "2023-01-10" @default.
• W4313894092 creator A5003109718 @default.
• W4313894092 creator A5031797084 @default.
• W4313894092 creator A5062962258 @default.
• W4313894092 creator A5087065184 @default.
• W4313894092 date "2023-01-07" @default.
• W4313894092 modified "2023-09-30" @default.
• W4313894092 title "Probing the Interactions of LRP1 Ectodomain-Derived Peptides with Fibrillar Tau Protein and Its Impact on Cellular Internalization" @default.
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