Pan RY, Ma J, Kong XX, Wang XF, Li SS, Qi XL, Yan YH, Cheng J, Liu Q, Jin W, Tan CH, Yuan Z. Sodium rutin ameliorates Alzheimer's disease-like pathology by enhancing microglial amyloid-β clearance. Sci Adv. 2019 Feb;5(2):eaau6328. Epub 2019 Feb 27 PubMed.
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University of Pittsburgh
This study tests the effect of Rutin (quercetin-3-rutinoside), a natural flavonoid with different biological functions that has been used in traditional medicines. The team processed rutin into sodium rutin using alkaline aqueous solution, significantly improving its water solubility and bioavailability. This makes it a much more promising drug than the natural compound.
The authors found a remarkable reduction of Aβ plaques in two mouse models of AD, namely APP/PSdE9 and 5xFAD. In both, the treatment started at a stage of already developed amyloid deposition so the effect could be characterized as therapeutic that reduces already formed amyloid. Pan et al. found that sodium rutin treatment did not affect APP processing and microglia proliferation but enhanced microglial recruitment around the plaques, which potentially can promote Aβ phagocytosis and clearance.
Furthermore, they found increased expression and recycling of phagocytic receptors such as GPR34, P2Y6, and others. However, in vitro experiments demonstrated that the phagocytic effect of sodium rutin was not affected by knockdown of phagocytic receptors such as Trem2, CR3, and MerTK.
To investigate the effect of sodium rutin on the phagocytic receptor Trem2 further, the authors used Trem2-deficient mice. Interestingly, the amyloid pathology in Trem2-deficient AD mice was ameliorated by sodium rutin treatment similarly as in Trem2-WT mice. Together, the in vitro and in vivo data suggest that at least these phagocytic receptors are not essential for the sodium rutin-mediated enhancement of Aβ phagocytosis and clearance.
Finally, the authors demonstrated that sodium rutin promotes a metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS (oxidative phosphorylation), which could provide microglia with sufficient energy (ATP) for Aβ clearance.
This is a very interesting and important study that proposes sodium rutin as a potential candidate for AD treatment through amelioration of neuroinflammation.
The number of mice per group is low. For example, the effect on amyloid deposition is analyzed on 14 to 18 slices from three mice per group (Fig.3). For some of the experiments (Fig.4) the data are presented as number of plaques, but it is not clear from how many mice are these plaques were collected.
View all comments by Radosveta KoldamovaIndiana University School of Medicine
Pan et al. report that oral administration of the flavonoid rutin to mouse models of Alzheimer’s disease results in amelioration of cognition deficits as well as a broad array of AD-related phenotypes. They report a dramatic reduction in plaque burden, an increase in plaque-associated microglia, enhanced phagocytic activity, and reduction in neuroinflammation. Remarkably, rutin elicits a robust increase in microglial (but not neuronal) oxidative metabolism. Indeed, it appears to be an elixir.
The novelty of this study arises principally from the reformulation of the compound as a sodium salt, improving its aqueous solubility. Previous studies reported in 2014 found salutary effects in an AD model on a more restricted range of endpoints, thus conceptually the study doesn’t break much new ground. There are >6,000 papers investigating the actions of rutin. There are myriad mechanisms of action that have been described, most prominently anti-oxidative and anti-inflammatory. The present study does not explore the underlying mechanism for any of rutin’s positive effects and it is difficult to understand how they are achieved and unlikely they can be ascribed to any single mechanism. It is notable that despite the very extensive study of this natural product there are few, if any, credible examples of its actions in humans. This raises the question of whether the robust effects of rutin (or maybe other flavonoids) observed in rodents in a large number of experimental settings are at all relevant in humans.
One of the most provocative findings is that rutin treatment results in a shift in the relative contribution of mitochondrial oxidative phosphorylation to microglial metabolism. This finding is of considerable significance and it is not clear how rutin might effect this change. I am not persuaded that overall microglial energetics is rate-limiting for phagocytosis. The authors state that the ability of rutin to enhance phagocytosis is due to induction of phagocytic receptors. This is an overstatement. They only have a correlation.
There are a few technical issues that need to be considered, most prominently the use of mice over a period of four to eight months of age in 5XFAD mice and six to 13 month APP/PS1 for behavioral experiments and synapse analysis. This is problematic as this spans the period in which rapid plaque deposition is occurring, and unless the cohorts were tightly matched for age and sex it is hard to understand how they achieve statistical significance. In our experience, it is hard to detect a genotype effect in the 5XFAD mice at four months. The change in synapse number and morphology is very small and of questionable biological significance. The ages of the animals were not stated for the other experiments (I didn’t have access to the supplemental material) and if there is a similar spread in ages it colors the interpretation of the data significantly.
View all comments by Gary LandrethMake a Comment
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