Alzheimer's disease (AD), a progressive neurodegenerative disorder, is one of the leading causes of dementia worldwide, and currently has no definitive cure. Although antibody-based therapies that target amyloid β (Aβ) have recently been developed, their clinical effectiveness remains limited. These treatments can be costly and cause immune-related side effects, highlighting the need for safer, affordable, and widely accessible approaches that can slow the progression of AD.

In a new study, made available online on October 30, 2025, in Neurochemistry International, researchers from Kindai University and collaborating institutions discovered that oral administration of arginine, a naturally occurring amino acid and safe chemical chaperone, effectively suppresses Aβ aggregation and its toxic effects in animal models of AD. The researchers emphasized that although arginine is available as an over-the-counter dietary supplement, the dosage and administration protocol employed in this study was optimized for research purposes and does not correspond to commercially available formulations.

The research team included Graduate Student Kanako Fujii and Professor Yoshitaka Nagai from the Department of Neurology, Kindai University Faculty of Medicine, Osaka, and Associate Professor Toshihide Takeuchi from the Life Science Research Institute, Kindai University, Osaka.

Using in vitro assays, the researchers first demonstrated that arginine can inhibit the formation of Aβ42 aggregates in a concentration-dependent manner. Building on these findings, the team evaluated oral arginine in two established AD models:

• A Drosophila model, expressing Aβ42 with the Arctic mutation (E22G)
• An App^NL-G-F knock-in mouse model, carrying three familial AD mutations

In both models, arginine administration significantly reduced Aβ accumulation and alleviated Aβ-induced toxicity.

"Our study demonstrates that arginine can suppress Aβ aggregation both in vitro and in vivo," explains Prof. Nagai. "What makes this finding exciting is that arginine is already known to be clinically safe and inexpensive, making it a highly promising candidate for repositioning as a therapeutic option for AD."

In the mouse model, oral arginine significantly decreased amyloid plaque deposition and lowered insoluble Aβ42 levels in the brain. Moreover, arginine-treated mice showed improved behavioral performance and reduced expression of pro-inflammatory cytokine genes associated with neuroinflammation, one of the key pathological features of AD. These results suggest that arginine's protective effects extend beyond aggregation inhibition to include broader neuroprotective and anti-inflammatory actions.

"Our findings open up new possibilities for developing arginine-based strategies for neurodegenerative diseases caused by protein misfolding and aggregation," notes Prof. Nagai. "Given its excellent safety profile and low cost, arginine could be rapidly translated to clinical trials for Alzheimer's and potentially other related disorders."

This research underscores the potential of drug repositioning-repurposing existing, safe compounds for new therapeutic uses-as an efficient pathway toward accessible Alzheimer's treatments. Because arginine is already used clinically in Japan and has demonstrated high safety and brain permeability, it may overcome several early barriers faced by conventional drug development.

The researchers note that further preclinical and clinical studies are needed to determine whether these therapeutic effects can be replicated in humans and to establish optimal dosing regimens. Nonetheless, the present findings provide compelling proof of concept that simple nutritional or pharmacological supplementation could mitigate amyloid pathology and improve neurological outcomes.

This study not only deepens our understanding of Aβ aggregation dynamics but also highlights a readily implementable and cost-effective strategy that could ultimately benefit the growing global population affected by AD.