The amino acid arginine has been shown to act as a chaperone, or improve the ability of existing chaperone molecules to reduce aggregation of misfolded proteins such as the amyloid-β associated with the development of Alzheimer’s disease. Researchers here supplement the diets of mice with sizable doses of arginine in order to produce effects on amyloid-β aggregation; the equivalent dose in humans would be something like 1 gram per kilogram of body weight, daily. One caveat is that the mouse model of Alzheimer’s used here is relevant to familial early onset Alzheimer’s rather than the much more common sporadic late onset form of the condition. Nonetheless, it is an interesting study.
Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer’s disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain.
In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an AppNL-G-F knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated AppNL-G-F knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes.
These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.
