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

Abstract

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 Aβ 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.

Treatment with Bifidobacteria can suppress Aβ accumulation and neuroinflammation in APP/PS1 mice

“…Exposure to microbial amyloid may cause misfolding of amyloid in the brain (Cerovic, Forloni & Balducci, 2019). Gv-971, a new anti-AD drug recently launched in China, can remodel the balance of gut microflora, normalize disordered metabolites to reduce Aβ deposition, and ultimately improve cognitive function (Wang et al, 2019a;Wang et al, 2019b). In view of this, probiotics and prebiotics may effectively fight against dementia, which is considered as an important progress in the field of AD.…”

“…In the past few decades, people have conducted extensive research on AD, but its pathogenesis is not clear, and no effective treatment has yet been found. Previous AD studies have focused on brain-related aspects such as the production and degradation of Aβ and abnormal phosphorylation of tau (Wang et al, 2019a;Wang et al, 2019b). In recent years, the gut microbiota has been implicated in the occurrence and progression of AD has become a research hotspot (Vogt et al, 2017).…”

Alzheimer’s Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models

“…No significant differences in either α- or β-diversity have been observed in 5xFAD mice at 9–10 weeks old [ 133 ], although α-diversity is lower in these mice by 6 and 12 months of age [ 134 ]. Nevertheless, α-diversity, that conveys the diversity of species within a single sample, is significantly higher in wildtype mice compared to APP/PS1 mice by 9 months of age [ 135 ], although other studies have reported higher α-diversity in the microbiota of APP/PS1 mice at the same age [ 90 ]. It also seems that α-diversity is diminished with aging in APP/PS1 mice, as an indication of a worse health status of the host with aging [ 132 ].…”

“…It also seems that α-diversity is diminished with aging in APP/PS1 mice, as an indication of a worse health status of the host with aging [ 132 ]. On the other hand, β-diversity shows significant differences in the microbiome composition of APP/PS1 mice by 2, 6 [ 90 ] and 9 months of age [ 135 ] when compared with their wildtype counterparts. So, as disease progresses a marked temporal shift in the taxonomic distribution of principal phyla is detected, and the Firmicutes / Bacteroidetes ratio increases in APP/PS1 [ 107 ] and 5xFAD mice [ 131 , 134 ] in an age-dependent manner.…”

Microbiota modulation as preventative and therapeutic approach in Alzheimer’s disease

“…Treatment with jatrorrhizine, a main component of Coptidis rhizome, a traditional Chinese herbal, alleviated learning and memory deficits, reduced the levels of Ab plaques in the cortex and hippocampus of APP/PS1 mice. Jatrorrhizine administration clearly affected mouse microbiota modulating the relative abundance of the most predominant phylum Firmicutes and Bacteroidetes in transgenic mice [175]. Also calorie restriction (CR) was effective in promoting neuroprotective effects and health benefits in different animal models, being also able to counteract AD symptoms [176][177][178].…”