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7-α-O-Methylmorroniside ameliorated brain injury in 5×FAD mice by regulating the gut microbiome and NMDAR2B
Fengxiao Hao1,2, Mengnan Zeng1,2, Bing Cao1,2
1College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China.
Abstract:
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline. 7-α-O-Methylmorroniside (MorA), an iridoid glycoside extracted from Cornus officinalis Sieb. et Zucc., has been shown to have neuroprotective effects, but the mechanism of its anti-AD effect has not been clarified. In the present study, we investigated the mechanism by which MorA ameliorated brain injury in 5×FAD mice by using gut microbiota (GM) combined with in vitro and in vivo pharmacological experiments. Behavioral tests revealed that MorA could enhance learning and memory ability and improve cognitive impairment. The results of pathology, flow cytometry and biochemical indexes showed that MorA could reduce the levels of neuronal apoptosis, oxidative stress, Aβ1-40, Aβ1-42, p-Tau, and inflammatory factors in the mouse brain tissues, and improve brain damage. 16S rDNA sequencing showed that MorA increased the abundance of the beneficial bacterium Lactobacillus and decreased the abundance of the inflammation-associated Muribaculaceae and Prevotellaceae, and that these differential bacteria were closely associated with brain biochemical indicators. In addition, pathway enrichment analysis, Western blot and molecular docking results showed that the ameliorative effect of MorA on brain injury in 5×FAD mice was closely related to NMDAR2B. Next, an inhibitor of NMDAR2B was added to Aβ25-35-induced N9 and PC12 cells to further investigate whether the effect of MorA on AD was mediated through NMDAR2B. In conclusion, MorA ameliorated brain injury in 5×FAD mice by restoring GM homeostasis and inhibiting NMDAR2B.
Insights
7-α-O-Methylmorroniside (MorA) improves Alzheimer's disease (AD) by restoring gut microbiota balance and inhibiting NMDAR2B, enhancing cognitive function and reducing brain injury in mice.
Area of Science:
- Neuroscience
- Pharmacology
- Microbiology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder causing cognitive decline.
- The neuroprotective mechanism of 7-α-O-Methylmorroniside (MorA), an iridoid glycoside from *Cornus officinalis*, against AD remains unclear.
- Investigating MorA's anti-AD effects requires understanding its impact on gut microbiota and molecular pathways.
Purpose of the Study:
- To elucidate the mechanism of MorA's ameliorative effects on brain injury in a mouse model of Alzheimer's disease (5×FAD mice).
- To evaluate the combined role of gut microbiota (GM) modulation and pharmacological actions of MorA.
- To determine the specific molecular targets, such as NMDAR2B, involved in MorA's therapeutic effects.
Main Methods:
- Utilized 5×FAD mice for *in vivo* studies, alongside *in vitro* cell experiments.
- Conducted behavioral tests, pathology assessments, flow cytometry, and biochemical analyses.
- Employed 16S rDNA sequencing for gut microbiota profiling, Western blot, and molecular docking for target identification.
Main Results:
- MorA significantly improved learning and memory, enhancing cognitive function in 5×FAD mice.
- MorA reduced neuronal apoptosis, oxidative stress, amyloid-beta (Aβ) levels (Aβ1-40, Aβ1-42), phosphorylated tau (p-Tau), and neuroinflammation.
- MorA modulated gut microbiota composition, increasing *Lactobacillus* and decreasing Muribaculaceae and Prevotellaceae, which correlated with brain health indicators. The mechanism involved inhibition of NMDAR2B.
Conclusions:
- MorA ameliorates brain injury in Alzheimer's disease models by restoring gut microbiota homeostasis.
- The therapeutic effects of MorA are linked to the inhibition of NMDAR2B signaling.
- MorA demonstrates potential as a therapeutic agent for Alzheimer's disease, acting through both gut microbiota modulation and direct neuronal pathways.
