Jatrorrhizine Balances the Gut Microbiota and Reverses Learning and Memory Deficits in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is a complex disorder influenced by both genetic and environmental components and has become a major public health issue throughout the world. Oxidative stress and inflammation play important roles in the evolution of those major pathological symptoms. Jatrorrhizine (JAT), a main component of a traditional Chinese herbal, coptidis rhizome, has been shown to have neuroprotective effects and we previously showed that it is also able to clear oxygen free radicals and reduce inflammatory responses. In this study, we demonstrated that JAT administration could alleviate the learning and memory deficits in AD. Furthermore, we also found that JAT treatment reduced the levels of Aß plaques in the cortex and hippocampus of APP/PS1 double-transgenic mice. Other studies suggest that there are gut microbiome alterations in AD. In order to explore the underlying mechanisms between gut microbiota and AD, DNA sequencing for 16s rDNA V3-V4 was performed in fecal samples from APP/PS1 transgenic mice and C57BL/6 wild-type (WT) mice. Our results indicated that APP/PS1 mice showed less Operational Taxonomic Units (OTUs) abundance in gut microbiota than WT mice and with different composition. Furthermore, JAT treatment enriched OTUs abundance and alpha diversity in APP/PS1 mice compared to WT mice. High dose of JAT treatment altered the abundance of some specific gut microbiota such as the most predominant phylum Firmicutes and Bacteroidetes in APP/PS1 mice. In conclusion, APP/PS1 mice display gut dysbiosis, and JAT treatment not only improved the memory deficits, but also regulated the abundance of the microbiota. This may provide a therapeutic way to balance the gut dysbiosis in AD patients.

Jatrorrhizine Protects Against Okadaic Acid Induced Oxidative Toxicity Through Inhibiting the Mitogen-Activated Protein Kinases Pathways in HT22 Hippocampal Neurons.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposit of amyloid plaques and neurofibrillary tangles and oxidative stress plays an essential role in the pathogenesis of AD. Jatrorrhizine (JAT), a Coptidis Rhizome, has multiple biological functions such as anti-oxidation and anti-inflammation. Herein, we investigated the neuroprotective effects of JAT on okadaic acid (OA)- induced cytotoxicity and apoptosis in HT22 cells. Following the exposure to 80 nmol/L OA for 12h, the reduction in cell survival, activities of superoxide dismutase, glutathione peroxidase and mitochondria membrane potential has been shown in HT22 cells. In contrast, OA increased levels of lactate dehydrogenase, malondialdehyde production and intracellular reactive oxygen species. OA also enhanced the expression of Bax but decreased the levels of Bcl-2, OA also upregulated the expression of cleaved caspase-3, phosphorylated extracellular signal-regulated kinases 1/2, phosphorylated c-Jun N-terminal kinases, phosphorylated p38 and NF-kappa B p65 subunit in HT22 cells and this up-regulation was attenuated by JAT which was pre-incubated for 12h in the cells prior to OA exposure. In conclusion, our data present the protective role of JAT in OA induced cytotoxicity, via its antioxidant and anti-apoptotic properties by inhibiting the mitogen-activated protein kinases pathways in HT22 hippocampal neurons. These results indicate that JAT may be the potential target to treat AD induced by oxidative stress and apoptosis.