Author Identifier (ORCID)
Abstract
Background/Objectives: Effective disease-modifying therapies targeting pathogenic proteins associated with Alzheimer’s disease (AD) remain limited. This study investigated the therapeutic potential of the neuroprotective, cationic arginine-rich peptide R18D to mitigate the pathogenic effects of amyloid-beta (Aβ) and tau associated with AD.
Methods: R18D was examined for its ability to inhibit Aβ aggregation in a cell-free assay, attenuate Aβ-induced cytotoxicity in MC65 cells, and suppress intracellular tau aggregation in two neural cell models. Intracellular tau aggregation was quantified using a homogeneous time-resolved fluorescence assay. Additionally, a pilot pharmacokinetic study of R18D was conducted in mice following oral gavage administration.
Results: In the cell-free assay, R18D inhibited Aβ aggregation by up to 65%. In human MC65 cells induced to overexpress APP-C99 and accumulate Aβ, treatment with R18D inhibited cellular toxicity by as much as 100%. Preformed tau seeds were applied to human SH-SY5Y cells and rat primary cortical neurons to induce intracellular tau aggregation, and tau levels were quantified after 48 h. Exposure to tau seeds induced robust tau aggregation in both cellular models, which was significantly attenuated by R18D treatment, reducing aggregation by 34.8% in SH-SY5Y cells and 49.9% in cortical neurons. Pharmacokinetic studies demonstrated that R18D was detectable in plasma at 30 and 60 min following oral administration in mice.
Conclusions: Together, these results demonstrate that R18D can modulate both Aβ and tau pathologies in vitro and is orally bioavailable, supporting its further evaluation as a therapeutic candidate for AD and other tau-associated neurodegenerative disorders.
Keywords
Alzheimer’s disease, amyloid-beta, cationic arginine-rich peptides, MC65 cells, primary cortical neurons, R18D, SH-SY5Y cells, tau protein, tau seeds
Document Type
Journal Article
Date of Publication
7-1-2026
Article Number
1564
E-ISSN
22279059
Volume
14
Issue
7
Publication Title
Biomedicines
Publisher
MDPI
School
Centre of Excellence for Alzheimer's Disease Research and Care / School of Medical and Health Sciences
RAS ID
101961
Funding Information
This research was funded by The Perron Institute for Neurological and Translational Science, Department of Neurosurgery, SCGH, Argenica Therapeutics, and philanthropic donations from Jim Litis and the Houston Family.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Recommended Citation
Bagda, V., Farooz, Z. H., Knuckey, N. W., South, S. M., Gribble, S. K., Tomar, M., Bharadwaj, P., Ariyath, A., Taddei, K., Martins, R. N., & Meloni, B. P. (2026). The poly-arginine peptide R18D inhibits amyloid-beta (Aβ) aggregation and Aβ-induced cytotoxicity, reduces intracellular tau aggregation, and exhibits oral bioavailability. Biomedicines, 14(7), 1564. https://doi.org/10.3390/biomedicines14071564