Want more evidence of the importance of microglia for Alzheimer’s disease? A study in the February 27 Science Advances suggests that spicing up the metabolism of these cells can tamp down Alzheimer’s pathology. Researchers led by Zengqiang Yuan at the Beijing Institute of Basic Medical Sciences investigated the effects of a flavonoid salt, sodium rutin, in two AD models. After consuming the salt for several months, the transgenic mice accumulated fewer plaques than untreated mice, while maintaining synapses and memory at wild-type levels. The authors attributed these improvements to healthier microglia and less inflammation. They report that cultured microglia exposed to sodium rutin expressed more phagocytic receptors, produced fewer pro-inflammatory cytokines, and made more ATP. A larger number of microglia surrounded plaques in treated mice than controls, and the cells internalized more Aβ.
- The flavonoid sodium rutin stimulates microglial metabolism.
- It boosts microglial phagocytosis of plaques, and lowers amyloid pathology in AD mouse models.
“This is a very interesting and important study that proposes sodium rutin as a potential candidate for AD treatment, through its amelioration of neuroinflammation,” Radosveta Koldamova at the University of Pittsburgh wrote to Alzforum. However, she cautioned that the authors examined but a handful of mice per group, highlighting the importance of replicating these findings in other studies. In the AD field, many treatments have worked in mice but failed to translate to people.
Rutin occurs naturally in plants such as apples, citrus fruits, green tea, and buckwheat. It acts as an antioxidant and anti-inflammatory, and has been found to inhibit Aβ aggregation in vitro (Jiménez-Aliaga et al., 2011; Wang et al., 2012). A previous study reported less neuroinflammation, fewer Aβ oligomers, and better memory in transgenic mice that consumed rutin (Xu et al., 2014). Other groups noted a beneficial effect of rutin on memory in injection models of neurotoxicity (Javed et al., 2012; Moghbelinejad et al., 2013; Choi et al., 2015).
However, the compound dissolves poorly in water, limiting its bioavailability. To get around this limitation, first author Rui-Yuan Pan dissolved rutin in sodium hydroxide, then purified the salt. Sodium rutin was 200-fold more soluble than its precursor, and achieved fivefold higher concentration in mouse serum. The compound crosses the blood-brain barrier, appearing in brain tissues two hours after ingestion. The authors did not report the concentration in brain.
Pan administered 0.25 mg/ml sodium rutin in water to six-month-old APP/PS1 mice for seven months. At 13 months, treated animals had half as many amyloid plaques in the prefrontal cortex as untreated controls did. They had less microgliosis, astrogliosis, and pro-inflammatory cytokines, but higher levels of anti-inflammatory cytokines such as IL-10. Treatment maintained dendritic spine density at wild-type levels, and rescued performance in the Morris water maze. In a second mouse model, 5xFAD, sodium rutin treatment lowered plaque burden by two-thirds and rescued long-term potentiation in slices. For behavioral studies, the authors analyzed about a dozen mice per group, while pathology studies used three to six mice per group.
How might sodium rutin produce these effects in the brain? The authors report that expression of several microglial phagocytic receptors, including TREM2, CR3, GPR34, MerTK, and P2Y6, bumped up by 50 percent or more in prefrontal cortex of treated APP/PS1 mice. Sodium rutin doubled the amount of TREM2 in microglia and enhanced its recycling to the cell surface. The authors did not report expression data for the 5xFAD mice.
TREM2 helps maintain mitochondrial energy production (Aug 2017 news). This led the authors to measure metabolism in cultured microglia exposed to sodium rutin. The treatment increased ATP production and oxygen consumption, they report. Sodium rutin localized to mitochondria in these cells. When the authors tested sodium rutin on microglia from TREM2 knockout mice, which have impaired oxidative phosphorylation, the treatment rescued ATP production. Thus, the authors concluded, the effects of sodium rutin do not depend on TREM2.
Would fitter mitochondria facilitate phagocytosis, which makes high energy demands on the cell? In support of this, the authors measured twice as many CD68-positive phagosomes and four times as much internalized Aβ in the prefrontal cortices of treated than untreated APP/PS1 mice. In addition, more microglia clustered around plaques in treated mice (see image above).
Overall, the data so far suggest that sodium rutin exerts its effects mainly through microglia, Yuan told Alzforum. He said that tracing experiments with biotinylated sodium rutin showed that it appeared almost exclusively in microglia in mouse cortex. In addition, the flavonoid had no effect on oxidative phosphorylation in cultured neurons or astrocytes. In future work, Yuan is searching for the cellular targets of sodium rutin to determine how it upregulates receptors and revs up metabolism. He hopes to test the compound in clinical trials.—Madolyn Bowman Rogers
Research Models Citations
- Jiménez-Aliaga K, Bermejo-Bescós P, Benedí J, Martín-Aragón S. Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci. 2011 Dec 19;89(25-26):939-45. PubMed.
- Wang SW, Wang YJ, Su YJ, Zhou WW, Yang SG, Zhang R, Zhao M, Li YN, Zhang ZP, Zhan DW, Liu RT. Rutin inhibits β-amyloid aggregation and cytotoxicity, attenuates oxidative stress, and decreases the production of nitric oxide and proinflammatory cytokines. Neurotoxicology. 2012 Jun;33(3):482-90. PubMed.
- Xu PX, Wang SW, Yu XL, Su YJ, Wang T, Zhou WW, Zhang H, Wang YJ, Liu RT. Rutin improves spatial memory in Alzheimer's disease transgenic mice by reducing Aβ oligomer level and attenuating oxidative stress and neuroinflammation. Behav Brain Res. 2014 May 1;264:173-80. Epub 2014 Feb 7 PubMed.
- Javed H, Khan MM, Ahmad A, Vaibhav K, Ahmad ME, Khan A, Ashafaq M, Islam F, Siddiqui MS, Safhi MM. Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience. 2012 May 17;210:340-52. PubMed.
- Moghbelinejad S, Nassiri-Asl M, Naserpour Farivar T, Abbasi E, Sheikhi M, Taghiloo M, Farsad F, Samimi A, Hajiali F. Rutin activates the MAPK pathway and BDNF gene expression on beta-amyloid induced neurotoxicity in rats. Toxicol Lett. 2013 Oct 20;224(1):108-113. PubMed.
- Choi JY, Lee JM, Lee DG, Cho S, Yoon YH, Cho EJ, Lee S. The n-Butanol Fraction and Rutin from Tartary Buckwheat Improve Cognition and Memory in an In Vivo Model of Amyloid-β-Induced Alzheimer's Disease. J Med Food. 2015 Jun;18(6):631-41. Epub 2015 Mar 18 PubMed.
- 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.