The subject of this blog is the study by Yan Xu et al., “Fucoidan Improves D-Galactose-Induced Cognitive Dysfunction by Promoting Mitochondrial Biogenesis and Maintaining Gut Microbiome Homeostasis.” The study aimed to explore the protective impact of fucoidan from Saccharina japonica in D-galactose-induced cognitive impairment and its mechanism.
Fucoidan, a natural substance that shows potential, is primarily a sulfated polysaccharide made of sulfate groups and L-fucose. Fucoidan has a wide range of biological and pharmacological activities, including anticancer, anticoagulant, antiviral, and anti-inflammatory properties.
Initially, the Y-maze test and MWM were used to assess cognitive decline in rats that had been exposed to D-galactosidase. The Y-maze data showed that the exploration time of the novel arm was significantly shortened in D-galactosidase-exposed rats. According to the Morris Water Maze (MWM) findings, the escape latency was significantly prolonged, the number of times the target quadrant was crossed was diminished, and the duration spent in the target quadrant was decreased in the D-galactosidase-treated rats. Exposure to D-galactosidase may cause damage to the spatial cognition, memory, and learning capabilities of rats. However, the findings implied that fucoidan could possibly help to diminish the spatial learning and memory problems in rats that were exposed to D-galactosidase, and it could also improve the organizational behavior disorder. This implies fucoidan could potentially shield the brain, helping to recover cognitive and memory function.
The data also showed that in hippocampal tissues of D-galactosidase-exposed rats, the number of normal cells in the CA1 and DG regions in Nissl staining was significantly decreased, and the number of solid contractile cells and disordered cell arrangement was increased. Fucoidan treatment resulted in both reduced cellular damage and a considerable increase in cell numbers.
Elevated oxidative stress levels are the primary cause of inducible neuron loss and cognitive impairment. Overproduction of reactive oxygen species and dysfunction of antioxidant defense mechanisms are symptoms of oxidative stress. In the study, as Figure 1 shows, fucoidan significantly reduced ROS levels and MDA activity and restored CAT, SOD, and GSH-Px levels in D-galactosidase (D-galactosidase)-exposed rats.
Elevated oxidative stress is the primary factor behind the loss of neurons and cognitive decline, with oxidative stress manifesting through excessive reactive oxygen species and impaired antioxidant defenses. In this study, fucoidan significantly reduced ROS levels and MDA activity and restored CAT, SOD, and GSH-Px levels in rats exposed to D-galactosidase.
Subsequently, the functionality of mitochondria in hippocampal tissue was assessed by measuring ATP levels and mtDNA copy number. The results showed that mitochondrial ATP content was significantly decreased in rats exposed to D-galactosidase. The results showed that fucoidan prevented D-galactosidase-induced ATP reduction, and the ATP content in the LF and HF groups similarly returned to normal levels. In addition, mtDNA copy number, an indicator of mitochondrial damage, was significantly decreased in the hippocampus of rats exposed to D-galactosidase, whereas fucoidan could significantly restore mtDNA copy number. Research has shown that fucoidan significantly reverses mitochondrial damage and exerts neuroprotective effects by inhibiting the decrease in ATP content in hydrogen peroxide-induced neurotoxicity and trimethyltin-induced cognitive impairment models. Furthermore, fucoidan might increase the amount of mtDNA in models of liver damage caused by ethanol. This proves that fucoidan can regulate ATP content and mtDNA copy number.
According to this research, fucoidan notably decreases the presence and fluorescent strength of the fission protein DRP1, while boosting the presence of the fusion protein MFN2 in rats exposed to D-galactosidase.
It is mitochondrial biogenesis that controls mitochondrial turnover and number, and reduced mitochondrial biogenesis may lead to mitochondrial dysfunction. PGC-1α, a transcriptional coactivator, is important for mitochondrial biogenesis and mitochondrial function. The interaction of PGC-1α with NRF1 elevates its expression, which then increases the expression of TFAM and facilitates the replication of mtDNA. Recently, it has been shown that reduced expression of PGC-1α-NRF1-TFAM was observed in AD patients. The purpose of this study was to assess the advantages of fucoidan concerning mitochondrial biogenesis in D-galactosidase-treated rats. Western blotting results showed that fucoidan significantly increased the expression levels of PGC-1α, NRF1, and TFAM. This suggests that fucoidan may promote mitochondrial biogenesis by promoting the PGC-1α-NRF1-TFAM signaling pathway, which may help improve mitochondrial dysfunction.
APN, or Adiponectin, is a regulator of metabolism, increases insulin sensitivity, and also has a variety of effects on the nervous system. AMP-activated protein kinase (AMPK) is not only significant in the energy metabolism of hippocampal tissue cells, but it also plays a role in preventing brain cognitive dysfunction, which is achieved through the regulation of neuroinflammation, autophagy, and apoptosis processes. AMPKα and p-AMPKα (Thr172), which are members of the AMPK family, can activate silent information regulator of transcription 1 (SIRT1). Evidence suggests SIRT1 is significant in averting several neurological diseases, with its impact on oxidative stress, energy metabolism, mitochondrial function, and autophagy considered the underlying processes.
Using Western blotting, they subsequently observed the levels of APN, AMPKα, p-AMPKα (Thr172), and SIRT1 in the rat hippocampus; they also used immunofluorescence to assess the expression location and fluorescence strength of SIRT1. The results showed that the p-AMPKα (Thr172)/AMPKα ratio, APN and SIRT1 protein expression levels were decreased in D-galactosidase (D-galactosidase) exposed rats. This study indicated that the APN-AMPK-SIRT1 signaling pathway is related to the D-galactosidase-induced damage factor mechanism. After fucoidan administration, the p-AMPKα (Thr172)/AMPKα ratio, APN, and SIRT1 expression levels were significantly increased in the HF group. Furthermore, the fluorescence results of SIRT1 were consistent with the protein expression results. The study also suggests that fucoidan may regulate mitochondrial biogenesis, PGC-1α-NRF1-TFAM, by activating the APN-AMPK-SIRT1 pathway.
An imbalance in gut bacteria has been connected to various conditions, encompassing diabetes, atherosclerosis, and age-related cognitive problems. The abundance of microbiota in the cecal contents of each rat group was measured by 16S sequencing. As shown in Fig. 2, it was found that the abundance of Firmicutes in the cecal contents was significantly decreased, and the abundance of Bacteroidota was significantly increased after fucoidan intervention compared with the MOD group. Bacteroidota have more carbohydrate-degrading enzymes than Firmicutes, and functional oligosaccharides can create a superior growth environment for Bacteroidota compared to Firmicutes, which allows Bacteroidota to fully utilize carbohydrates as substrates.
Therefore, fucoidan intervention suppresses the abundance of Firmicutes and promotes the abundance of Bacteroidota. The potential mechanisms of the anti-inflammatory effect of fucoidan are the inhibition of the genus Firmicutes and the upregulation of the genus Bacteroidota. Compared with the MOD group, the abundance of the genus unclassified_Lachnospiraceae decreased and the abundance of the genus unclassified_Muribaculaceae increased after fucoidan intervention.
According to studies, Muribaculaceae may influence cognitive function in AD patients by managing oxidative stress, inflammation, and the microbiota-gut-brain axis. In addition, Akkermansia was the predominant bacterial group in the HF group in the LDA score. Studies have shown that the intake of Akkermansia can completely ameliorate intestinal disease and extend the healthy lifespan of aged mice. This may be connected to fucoidan’s role in safeguarding cognitive function. The data suggest that fucoidan can lessen inflammation, oxidative stress, and mitochondrial dysfunction, along with improving cognitive problems brought on by D-galactosidase, by modifying the structure and content of microbial communities in rats.
In conclusion, fucoidan was shown to reduce oxidative stress and inflammation levels, improve mitochondrial dysfunction, and alleviate D-galactosidase-induced cognitive impairment by regulating the APN-AMPK-SIRT1 signaling pathway and the homeostasis of the intestinal flora (See Figure 3). Fucoidan’s potential as a functional food to help prevent cognitive issues related to aging has been proposed. Additional studies on the mechanism of action in several rat tissues are essential for the progress of future research.
Source: Nutrients. 2024 May 17;16(10):1512. doi: 10.3390/nu16101512