2026
Biomedicines 2026 Jul:14(7), 1564; doi: 10.3390/biomedicines14071564
The Poly-Arginine Peptide R18D Inhibits Amyloid-Beta (Aβ) Aggregation and Aβ-Induced Cytotoxicity, Reduces Intracellular Tau Aggregation, and Exhibits Oral Bioavailability
Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia School of Human Sciences, The University of Western Australia, Nedlands, WA 6009, Australia Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA 6009, Australia Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, WA 6009, Australia Argenica Therapeutics, Nedlands, WA 6009, Australia School of Biological Sciences, The University of Western Australia, Crawley, WA 6009, Australia Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia Alzheimer’s Research Australia, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA 6009, Australia Medical School, The University of Western Australia, Nedlands, WA 6009, Australia Department of Biomedical Sciences, Macquarie University, Sydney, NSW 2109, Australia
Service type: Stock strains
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.
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