Version 1
: Received: 18 May 2023 / Approved: 19 May 2023 / Online: 19 May 2023 (08:06:10 CEST)
How to cite:
Reich, N.; Allsop, D.; Parkin, E.; Dawson, N. Liposome Nanoparticle Conjugation and Cell Penetrating Peptide Sequences (CPPs) Enhance the Cellular Delivery of the Tau Aggregation Inhibitor RI-AG03. Preprints2023, 2023051403. https://doi.org/10.20944/preprints202305.1403.v1
Reich, N.; Allsop, D.; Parkin, E.; Dawson, N. Liposome Nanoparticle Conjugation and Cell Penetrating Peptide Sequences (CPPs) Enhance the Cellular Delivery of the Tau Aggregation Inhibitor RI-AG03. Preprints 2023, 2023051403. https://doi.org/10.20944/preprints202305.1403.v1
Reich, N.; Allsop, D.; Parkin, E.; Dawson, N. Liposome Nanoparticle Conjugation and Cell Penetrating Peptide Sequences (CPPs) Enhance the Cellular Delivery of the Tau Aggregation Inhibitor RI-AG03. Preprints2023, 2023051403. https://doi.org/10.20944/preprints202305.1403.v1
APA Style
Reich, N., Allsop, D., Parkin, E., & Dawson, N. (2023). Liposome Nanoparticle Conjugation and Cell Penetrating Peptide Sequences (CPPs) Enhance the Cellular Delivery of the Tau Aggregation Inhibitor RI-AG03. Preprints. https://doi.org/10.20944/preprints202305.1403.v1
Chicago/Turabian Style
Reich, N., Edward Parkin and Neil Dawson. 2023 "Liposome Nanoparticle Conjugation and Cell Penetrating Peptide Sequences (CPPs) Enhance the Cellular Delivery of the Tau Aggregation Inhibitor RI-AG03" Preprints. https://doi.org/10.20944/preprints202305.1403.v1
Abstract
Given the pathological role of hyperphosphorylated Tau aggregation in Alzheimer’s disease (AD) our laboratory previously developed the novel Tau aggregation inhibitor peptide, RI-AG03. As Tau aggregates accumulate intracellularly, it is essential that Tau-targeting peptides efficiently traverse the cell membrane. In addition, these peptides need to avoid sequestration into cell organelles, particularly those involved in degradation, to ensure interaction with Tau in the cytoplasm. Here, we examine the cellular uptake and intracellular trafficking of RI-AG03 when the peptide is unconjugated or linked to nanoliposome carrier particles. The impact of adding the cell penetrating peptide (CPP) sequences, polyarginine (polyR) and transactivator of transcription (TAT), to RI-AG03 was also characterised. Our data show that the conjugation of CPP-containing RI-AG03 to liposomes dramatically increases cellular liposomes uptake. The majority of this uptake occurs via direct cell penetration. However, we find that macropinocytosis is also an important mechanism for unconjugated and RI-AG03-polyR-conjugated, but not RI-AG03-TAT-conjugated, liposome uptake. In agreement with this macropinocytosis-mediated internalisation, liposome lipids localise to lysosomes and macropinosomes following cellular uptake. However, while unconjugated RI-AG03 peptides also localise to lysosomes, liposome conjugation prevents this localisation, with the peptide detaching from the liposomes at the cell surface and evading organelle entrapment. Overall, this study demonstrates that CPP sequences and nanoliposomes carriers enhance the intracellular delivery of RI-AG03, furthering the possibility of the peptide’s use in targeting Tau pathology in AD.
Keywords
Alzheimer’s Disease; Tauopathy; Cell penetrating peptide; Polyarginine; TAT; Liposomes; Nanoparticles; Tau pathology; Tau aggregation inhibitor; Endocytosis
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
